Benzimidazole derivatives

ABSTRACT

Novel compounds of the formula I 
                         
in which
         D, X, X′, W, Y, T and R 1  are as defined in Patent claim  1 , are inhibitors of coagulation factor Xa and can be employed for the prophylaxis and/or therapy of thromboembolic diseases and for the treatment of tumours.

The invention relates to compounds of the formula I

in which

-   D is an aromatic carbocyclic or heterocyclic ring having from 0 to 4    N, O and/or S atoms which is unsubstituted or monosubstituted or    polysubstituted by Hal, A, OR², N(R²)₂, NO₂, CN, COOR² or CON(R²)₂,-   X and X′ are each, independently of one another, H, Hal, A, OR²,    N(R²)₂, NO₂, CN, COOR² or CON(R²)₂,-   R¹ is H or A,-   R² is H, A, —[C(R¹)₂]_(n)—Ar′, —[C(R¹)₂]_(n)-Het′,    —[C(R¹)₂]_(n)-cycloalkyl, —[C(R¹)₂]_(n)—N(R¹)₂ or —[C(R¹)₂]_(n)—OR¹,-   W is —[C(R²)₂]_(n)CONR²[C(R²)₂]_(n)—,    —[C(R²)₂]_(n)NR²CO[C(R²)₂]_(n)—, —[C(R²)₂]_(n)O[C(R²)₂]_(n)—,    —[C(R²)₂]_(n)NR²[C(R²)₂]_(n)—,    —[C(R²)₂]_(n)O[C(R²)₂]_(n)CONR²[C(R²)₂]_(n)—,    —[C(R²)₂]_(n)NR²[C(R²)₂]_(n)CONR²[C(R²)₂]_(n)—,    —[C(R²)₂]_(n)NR²COO[C(R²)₂]_(n)— or    —[C(R²)₂]_(n)S(O)_(m)[C(R²)₂]_(n)CONR²[C(R²)₂]_(n)—,-   Y is alkylene, cycloalkylene, Het-diyl or Ar-diyl,-   T is a monocyclic or bicyclic, saturated, unsaturated or aromatic    carbocyclic or heterocyclic ring having from 0 to 4 N, O and/or S    atoms which is unsubstituted or monosubstituted, disubstituted or    trisubstituted by ═O, ═S, ═NR², ═N—CN, ═N—NO₂, ═NOR², ═NCOR²,    ═NCOOR², ═NOCOR², R², Hal, —[C(R¹)₂]_(n)—Ar, —[C(R¹)₂]_(n)-Het,    —[C(R¹)₂]_(n)-cycloalkyl, OR², N(R²)₂, NO₂, CN, COOR², CON(R²)₂,    NR²COA, NR²SO₂A, COR² and/or S(O)_(m)A,-   A is unbranched or branched alkyl having 1-10 carbon atoms, in which    one or two CH₂ groups may be replaced by O or S atoms and/or by    —CH═CH— groups and/or in addition 1-7 H atoms may be replaced by F,-   Ar is phenyl, naphthyl or biphenyl, each of which is unsubstituted    or monosubstituted, disubstituted or trisubstituted by Hal, A, OR²,    N(R²)₂, NO₂, CN, COOR², CON(R²)₂, NR²COA, NR²CON(R²)₂, NR²SO₂A,    COR², SO₂N(R²)₂, S(O)_(m)A, —[C(R¹)₂]_(n)—COOR² or    —O—[C(R¹)₂]_(o)—COOR²,-   Ar′ is phenyl which is unsubstituted or monosubstituted,    disubstituted or trisubstituted by Hal, A, OR¹, N(R¹)₂, NO₂, CN,    COOR¹, CON(R¹)₂, NR¹COA, NR¹SO₂A, COR¹, SO₂N(R¹)₂, S(O)_(m)A,    —[C(R¹)₂]_(n)—COOR¹ or —O—[C(R¹)₂]_(o)—COOR¹,-   Het is a monocyclic or bicyclic, saturated, unsaturated or aromatic    heterocyclic ring having from 1 to 4 N, O and/or S atoms which is    unsubstituted or monosubstituted, disubstituted or trisubstituted by    carbonyl oxygen, ═S, ═N(R¹)₂, Hal, A, —[C(R¹)₂]_(n)—Ar,    —[C(R¹)₂]_(n)-Het′, —[C(R¹)₂]_(n)-cycloalkyl, —[C(R¹)₂]_(n)—OR²,    —[C(R¹)₂]_(n)—N(R²)₂, NO₂, CN, —[C(R¹)₂]_(n)—COOR²,    —[C(R¹)₂]_(n)—CON(R²)₂, —[C(R¹)₂]_(n)—NR²COA, NR²CON(R²)₂,    —[C(R¹)₂]_(n)—NR²SO₂A, COR², SO₂N(R²)₂ and/or S(O)_(m)A,-   Het′ is a monocyclic or bicyclic, saturated, unsaturated or aromatic    heterocyclic ring having from 1 to 4 N, O and/or S atoms which is    unsubstituted or monosubstituted or disubstituted by carbonyl    oxygen, ═S, ═N(R¹)₂, Hal, A, OR¹, N(R¹)₂, NO₂, CN, COOR¹, CON(R¹)₂,    NR¹COA, NR¹SO₂A, COR¹, SO₂N(R¹)₂ and/or S(O)_(m)A,-   Hal is F, Cl, Br or 1,-   m is 0, 1 or 2,-   n is 0, 1 or 2,-   o is 1, 2 or 3,    and pharmaceutically usable derivatives, solvates and stereoisomers    thereof, including mixtures thereof in all ratios.

The invention had the object of finding novel compounds having valuableproperties, in particular those which can be used for the preparation ofmedicaments.

It has been found that the compounds of the formula I and salts thereofhave very valuable pharmacological properties and are well tolerated. Inparticular, they exhibit factor Xa-inhibiting properties and cantherefore be employed for combating and preventing thromboembolicdisorders, such as thrombosis, myocardial infarction, arteriosclerosis,inflammation, apoplexia, angina pectoris, restenosis after angioplastyand claudicatio intermittens.

The compounds of the formula I according to the invention mayfurthermore be inhibitors of the coagulation factors factor VIIa, factorIXa and thrombin in the blood coagulation cascade.

Aromatic amidine derivatives having an antithrombotic action aredisclosed, for example, in EP 0 540 051 B1, WO 98/28269, WO 00/71508, WO00/71511, WO 00/71493, WO 00/71507, WO 00/71509, WO 00/71512, WO00/71515 and WO 00/71516. Cyclic guanidines for the treatment ofthromboembolic disorders are described, for example, in WO 97/08165.Aromatic heterocyclic compounds having a factor Xa inhibitory activityare disclosed, for example, in WO 96/10022. SubstitutedN-[(aminoiminomethyl)phenylalkyl]azaheterocyclylamides as factor Xainhibitors are described in WO 96/40679. Pyrazole derivatives aredisclosed in WO 01/29006 and WO 02/24690.

The antithrombotic and anticoagulant effect of the compounds accordingto the invention is attributed to the inhibitory action againstactivated coagulation protease, known by the name factor Xa, or to theinhibition of other activated serine proteases, such as factor VI la,factor IXa or thrombin.

Factor Xa is one of the proteases involved in the complex process ofblood coagulation. Factor Xa catalyses the conversion of prothrombininto thrombin. Thrombin cleaves fibrinogen into fibrin monomers, which,after crosslinking, make an elementary contribution to thrombusformation. Activation of thrombin may result in the occurrence ofthromboembolic disorders. However, inhibition of thrombin may inhibitthe fibrin formation involved in thrombus formation.

The inhibition of thrombin can be measured, for example by the method ofG. F. Cousins et al. in Circulation 1996, 94, 1705-1712.

Inhibition of factor Xa can thus prevent the formation of thrombin. Thecompounds of the formula I according to the invention and their saltsengage in the blood coagulation process by inhibiting factor Xa and thusinhibit the formation of thrombuses.

The inhibition of factor Xa by the compounds according to the inventionand the measurement of the anticoagulant and antithrombotic activity canbe determined by conventional in-vitro or in-vivo methods. A suitablemethod is described, for example, by J. Hauptmann et al. in Thrombosisand Haemostasis 1990, 63, 220-223.

The inhibition of factor Xa can be measured, for example by the methodof T. Hara et al. in Thromb. Haemostas. 1994, 71, 314-319.

Coagulation factor VIIa initiates the extrinsic part of the coagulationcascade after binding to tissue factor and contributes to the activationof factor X to give factor Xa. Inhibition of factor VIIa thus preventsthe formation of factor Xa and thus subsequent thrombin formation.

The inhibition of factor VIIa by the compounds according to theinvention and the measurement of the anticoagulant and antithromboticactivity can be determined by conventional in-vitro or in-vivo methods.A conventional method for the measurement of the inhibition of factorVIIa is described, for example, by H. F. Ronning et al. in ThrombosisResearch 1996, 84, 73-81.

Coagulation factor IXa is generated in the intrinsic coagulation cascadeand is likewise involved in the activation of factor X to give factorXa. Inhibition of factor IXa can therefore prevent the formation offactor Xa in a different way.

The inhibition of factor IXa by the compounds according to the inventionand the measurement of the anticoagulant and antithrombotic activity canbe determined by conventional in-vitro or in-vivo methods. A suitablemethod is described, for example, by J. Chang et al. in Journal ofBiological Chemistry 1998, 273, 12089-12094.

The compounds according to the invention may furthermore be used for thetreatment of tumours, tumour illnesses and/or tumour metastases. Acorrelation between tissue factor TF/factor VIIa and the development ofvarious types of cancer has been indicated by T. Taniguchi and N. R.Lemoine in Biomed. Health Res. (2000), 41 (Molecular Pathogenesis ofPancreatic Cancer), 57-59.

The publications listed below describe an antitumoural action of TF-VIIand factor Xa inhibitors for various types of tumour:

-   K. M. Donnelly et al. in Thromb. Haemost. 1998; 79: 1041-1047;-   E. G. Fischer et al. in J. Clin. Invest. 104: 1213-1221 (1999);-   B. M. Mueller et al. in J. Clin. Invest. 101: 1372-1378 (1998);-   M. E. Bromberg et al. in Thromb. Haemost. 1999; 82: 88-92

The compounds of the formula I can be employed as medicament activeingredients in human and veterinary medicine, in particular for thetreatment and prevention of thromboembolic disorders, such asthrombosis, myocardial infarction, arteriosclerosis, inflammation,apoplexia, angina pectoris, restenosis after angioplasty, claudicatiointermittens, venous thrombosis, pulmonary embolism, arterialthrombosis, myocardial ischaemia, unstable angina and strokes based onthrombosis.

The compounds according to the invention are also employed for thetreatment or prophylaxis of atherosclerotic diseases, such as coronaryarterial disease, cerebral arterial disease or peripheral arterialdisease. The compounds are also employed in combination with otherthrombolytic agents in myocardial infarction, furthermore forprophylaxis for reocclusion after thrombolysis, percutaneoustransluminal angioplasty (PTCA) and coronary bypass operations.

The compounds according to the invention are furthermore used for theprevention of rethrombosis in microsurgery, furthermore asanticoagulants in connection with artificial organs or in haemodialysis.

The compounds are furthermore used in the cleaning of catheters andmedical aids in patients in vivo, or as anticoagulants for thepreservation of blood, plasma and other blood products in vitro. Thecompounds according to the invention are furthermore used for diseasesin which blood coagulation makes a crucial contribution toward thecourse of the disease or represents a source of secondary pathology,such as, for example, in cancer, including metastasis, inflammatorydisorders, including arthritis, and diabetes.

The compounds according to the invention are furthermore used for thetreatment of migraine (F. Morales-Asin et al., Headache, 40, 2000,45-47).

In the treatment of the disorders described, the compounds according tothe invention are also used in combination with other thrombolyticallyactive compounds, such as, for example, with the “tissue plasminogenactivator” t-PA, modified t-PA, streptokinase or urokinase. Thecompounds according to the invention are administered either at the sametime as or before or after the other substances mentioned.

Particular preference is given to simultaneous administration withaspirin in order to prevent recurrence of the clot formation.

The compounds according to the invention are also used in combinationwith blood platelet glycoprotein receptor (IIb/IIIa) antagonists, whichinhibit blood platelet aggregation.

The invention relates to the compounds of the formula I and saltsthereof and to a process for the preparation of compounds of the formulaI according to claims 1-22 and pharmaceutically usable derivatives,solvates and stereoisomers thereof, characterised in that

-   a) for the preparation of a compound of the formula I in which    -   W is —[C(R²)₂]_(n)CONR²[C(R²)₂]_(n)—,        a compound of the formula II

in which

-   L is Cl, Br, I or a free or reactively functionally modified OH    group, and R¹, R², D, X, X′ and n are as defined in Claim 1,    with the proviso that any further OH and/or amino group present is    protected,    is reacted with a compound of the formula III    Z′-Y-T  III    in which-   Z′ is NHR² [C(R²)₂]_(n)—,-   and R², Y, T and n are as defined in Claim 1,-   and any protecting group is subsequently removed,-   b) and/or in that a radical T in a compound of the formula I is    converted into another radical T    by, for example,-   i) converting a sulfinyl compound into an imino compound,-   ii) removing an amino-protecting group,    and/or    a base or acid of the formula I is converted into one of its salts.

The invention also relates to the optically active forms(stereoisomers), the enantiomers, the racemates, the diastereomers andthe hydrates and solvates of these compounds. The term solvates of thecompounds is taken to mean adductions of inert solvent molecules ontothe compounds which form owing to their mutual attractive force.Solvates are, for example, mono- or dihydrates or alcoholates.

The term “pharmaceutically usable derivatives” is taken to mean, forexample, the salts of the compounds according to the invention andso-called prodrug compounds.

The term “prodrug derivatives” is taken to mean compounds of the formulaI which have been modified with, for example, alkyl or acyl groups,sugars or oligopeptides and which are rapidly cleaved in the organism toform the active compounds according to the invention.

These also include biodegradable polymer derivatives of the compoundsaccording to the invention, as described, for example, in Int. J. Pharm.115, 61-67 (1995).

The invention also relates to mixtures of the compounds of the formula Iaccording to the invention, for example mixtures of two diastereomers,for example in the ratio 01:01, 01:02, 01:03, 01:04, 01:05, 01:10, 1:100or 1:1000.

These are particularly preferably mixtures of stereoisomeric compounds.

For all radicals which occur more than once, such as, for example, A,their meanings are independent of one another.

Above and below, the radicals and parameters D, W, X, X′, Y, T and R¹are as defined under the formula I, unless expressly stated otherwise.

The following abbreviations are used below:

Ac acetyl BOC tert-butoxycarbonyl CBZ or Z benzyloxycarbonyl DCCIdicyclohexylcarbodiimide DCM dichloromethane DMF dimethylformamide EDCIN-ethyl-N,N′-(dimethylaminopropyl)carbodiimide EA ethyl acetate Et ethylFmoc 9-fluorenylmethoxycarbonyl HOBt 1-hydroxybenzotriazole Me methylMBHA 4-methylbenzhydrylamine Mtr 4-methoxy-2,3,6-trimethylphenylsulfonylHONSu N-hydroxysuccinimide OBut tert-butyl ester Oct octanoyl OMe methylester OEt ethyl ester POA phenoxyacetyl TFA trifluoroacetic acid Trttrityl (triphenylmethyl).

A is alkyl, is unbranched (linear) or branched, and has 1, 2, 3, 4, 5,6, 7, 8, 9 or 10 carbon atoms. A is preferably methyl, furthermoreethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl,furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl,1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl,1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or1,2,2-trimethylpropyl, furthermore preferably, for example,trifluoromethyl. A is very particularly preferably alkyl having 1, 2, 3,4, 5 or 6 carbon atoms, preferably methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl,pentafluoroethyl or 1,1,1-trifluoroethyl.

Alkoxy is preferably, for example, methoxy, ethoxy, propoxy, isopropoxy,butoxy, trifluoromethoxy or cyclopentoxy.

Cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl or cycloheptyl.

Alkylene is preferably methylene, ethylene, propylene, butylene,pentylene or hexylene, furthermore branched alkylene.

R¹ is H or A, where A is preferably alkyl having 1, 2, 3, 4, 5 or 6carbon atoms. R¹ is, in particular, H.

COR² is for example, CHO or —COA.

—COA (acyl) is preferably acetyl, propionyl, furthermore also butyryl,pentanoyl, hexanoyl or, for example, benzoyl.

Hal is preferably F, Cl or Br, but alternatively I.

“Poly”substituted means mono-, di-, tri-, tetra- or pentasubstituted.

Ar is preferably phenyl, naphthyl, each of which is unsubstituted ormono-substituted, disubstituted or trisubstituted by Hal, A, OH, NH₂,NO₂, CN, COOH, CONH₂, NHCOA, NHCONH₂, NHSO₂A, COH, SO₂NH₂, S(O)_(m)A,—(CH₂)_(n)—COOR² or —O—(CH₂)_(o)—COOR².

R² is preferably H, A or —[C(R¹)₂]_(n)—Ar′; particularly preferably H,methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, phenyl orbenzyl.

Ar is preferably phenyl, naphthyl or biphenyl, each of which isunsubstituted or monosubstituted, disubstituted or trisubstituted byHal, A, OR¹, N(R¹)₂, NO₂, CN, COOR¹, CON(R¹)₂, NR¹COA, NR¹CON(R¹)₂,NR¹SO₂A, COR¹, SO₂N(R¹)₂, S(O)_(m)A, —[C(R¹)₂]_(n)—COOR¹ or—O—[C(R¹)₂]_(o)—COOR¹, for example unsubstituted phenyl, naphthyl orbiphen-yl, furthermore preferably phenyl, naphthyl or biphenyl, each ofwhich is, for example, monosubstituted, disubstituted or trisubstitutedby A, fluorine, chlorine, bromine, iodine, hydroxyl, methoxy, ethoxy,propoxy, butoxy, pentyloxy, hexyloxy, nitro, cyano, formyl, acetyl,propionyl, trifluoromethyl, amino, methylamino, ethylamino,dimethylamino, diethylamino, benzyloxy, sulfonamido, methylsulfonamido,ethylsulfonamido, propylsulfonamido, butylsulfonamido,dimethylsulfonamido, phenylsulfonamido, carboxyl, methoxycarbonyl,ethoxycarbonyl or aminocarbonyl.

Ar′ has the same preferred meanings as Ar. Ar′ is very particularlypreferably phenyl.

Het is, for example, 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-,4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4-or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl,furthermore preferably 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-,-3- or -5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl,1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl,1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 3- or4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 4- or5-isoindolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-,5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-,4-, 5-, 6-, 7- or 8-quinolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 5-or 6-quinoxalinyl, 2-, 3-, 5-, 6-, 7- or 8-2H-benzo-1,4-oxazinyl,furthermore preferably 1,3-benzo-dioxol-5-yl, 1,4-benzodioxan-6-yl,2,1,3-benzothiadiazol-4- or -5-yl or 2,1,3-benzoxadiazol-5-yl.

The heterocyclic radicals may also be partially or fully hydrogenated.Het can thus also be, for example, 2,3-dihydro-2-, -3-, -4- or -5-furyl,2,5-dihydro-2-, -3-, -4- or 5-furyl, tetrahydro-2- or -3-furyl,1,3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-, -2-,-3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, 4- or -5-pyrrolyl,1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl,2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or-4-pyrazolyl, 1,4-dihydro-1-, -2-, -3- or -4-pyridyl,1,2,3,4-tetra-hydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-, 2-, 3- or4-piperidinyl, 2-, 3-, or 4-morpholinyl, tetrahydro-2-, -3- or-4-pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-, -4- or -5-yl, hexahydro-1-, -3-or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or3-piperazinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or-8-quinolyl, 1,2,3,4-tetrahydro-1-,-2-,-3-, -4-, -5-, -6-, -7- or-8-isoquinolyl, 2-, 3-, 5-, 6-, 7- or8-3,4-dihydro-2H-benzo-1,4-oxazinyl, furthermore preferably2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl,2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl,3,4-(difluoromethylenedioxy)phenyl, 2,3-dihydrobenzofuran-5- or 6-yl,2,3-(2-oxomethylenedioxy)phenyl or alternatively3,4-dihydro-2H-1,5-benzodioxepin-6- or -7-yl, furthermore preferably2,3-dihydrobenzofuranyl or 2,3-dihydro-2-oxofuranyl.

Het′ has the preferred meanings, such as Het.

T is preferably a monocyclic saturated or unsaturated carbocyclic orheterocyclic ring having 1 or 2 N and/or O atoms which is unsubstitutedor monosubstituted or disubstituted by ═O, ═S, ═NR¹, ═NOR¹, ═N—CN,═N—NO₂, ═NCOR¹, ═NCOOR¹ or ═NOCOR¹, A, Hal and/or S(O)_(m)A, where theterm heterocyclic ring is taken to mean, for example, phenyl orcyclohexyl, and the heterocyclic ring is as defined under Het.

T is, in particular, a monocyclic saturated or unsaturated heterocyclicring having 1 or 2 N and/or O atoms which is unsubstituted ormonosubstituted or disubstituted by ═O, ═S, ═NR¹ or ═NOR¹.

T is furthermore particularly preferably, for example, piperidin-1-yl,pyrrolidin-1-yl, pyridyl, morpholin-4-yl, piperazin-1-yl, pyrazin-1-yl,oxazolidin-3-yl, 2H-pyridazin-2-yl, azepan-1-yl,2-azabicyclo[2.2.2]octan-2-yl, pyrazol-2-yl, 1,2-dihydropyrazol-2-yl orphenyl, which may be monosubstituted, disubstituted or trisubstituted byA, Hal or S(O)_(m)A.

In a further particularly preferred embodiment, T is, for example,2-oxo-piperidin-1-yl, 2-oxopyrrolidin-1-yl, 2-oxo-1H-pyridin-1-yl,3-oxomorpholin-4-yl, 4-oxo-1H-pyridin-1-yl, 2,6-dioxopiperidin-1-yl,2-oxopiperazin-1-yl, 2-oxopyrazin-1-yl, 2,6-dioxopiperazin-1-yl,2,5-dioxopyrrolidin-1-yl, 2-oxo-1,3-oxazolidin-3-yl,3-oxo-2H-pyridazin-2-yl, 2-caprolactam-1-yl (=2-oxo-azepan-1-yl),2-hydroxy-6-oxopiperazin-1-yl, 2-azabicyclo[2.2.2]octan-3-on-2-yl,2-methoxy-6-oxopiperazin-1-yl, 5,6-dihydro-1H-pyrimidin-2-oxo-1-yl,2-iminopiperidin-1-yl, 2-iminopyrrolidin-1-yl, 2-imino-1H-pyridin-1-yl,3-iminomorpholin-4-yl, 4-imino-1H-pyridin-1-yl,2,6-diiminopiperidin-1-yl, 2-iminopiperazin-1-yl,2,6-diiminopiperazin-1-yl, 2,5-diiminopyrrolidin-1-yl,2-imino-1,3-oxazolidin-3-yl, 3-imino-2H-pyridazin-2-yl,2-iminoazepan-1-yl, 2-hydroxy-6-iminopiperazin-1-yl,2-methoxy-6-iminopiperazin-1-yl or pyridyl,

and the corresponding hydroxyimino, alkoxyimino and thioxo derivatives,or phenyl, which may be monosubstituted, disubstituted or trisubstitutedby A, Hal and/or S(O)_(m)A.

In a further particularly preferred embodiment, T is, for example,2-oxo-piperidin-1-yl, 2-oxopyrrolidin-1-yl, 2-oxo-1H-pyridin-1-yl,3-oxomorpholin-4-yl, 4-oxo-1H-pyridin-1-yl, 2,6-dioxopiperidin-1-yl,2-oxopiperazin-1-yl, 2,6-dioxopiperazin-1-yl, 2-oxopyrazin-1-yl,2,5-dioxopyrrolidin-1-yl, 2-oxo-1,3-oxazolidin-3-yl,3-oxo-2H-pyridazin-2-yl, 2-caprolactam-1-yl (=2-oxo-azepan-1-yl),2-hydroxy-6-oxopiperazin-1-yl, 2-azabicyclo[2.2.2]octan-3-on-2-yl,2-methoxy-6-oxopiperazin-1-yl, 5,6-dihydro-1H-pyrimidin-2-oxo-1-yl,2-iminopiperidin-1-yl, 2-iminopyrrolidin-1-yl or pyridyl, or phenyl,which may be monosubstituted, disubstituted or trisubstituted by A, Haland/or S(O)_(m)A.

In a further embodiment, T is preferably a monocyclic saturated orunsaturated carbocyclic or heterocyclic ring having 1 or 2 N and/or Oatoms which is monosubstituted or disubstituted by ═O, ═S, ═NR¹, ═NOR¹,═N—CN, ═N—NO₂, ═NCOR¹, ═NCOOR¹ or ═NOCOR¹, where the term carbocyclicring is taken to mean, for example, phenyl or cyclohexyl, and theheterocyclic ring is as defined under Het.

In a further embodiment, T is, in particular, a monocyclic saturated orunsaturated heterocyclic ring having 1 or 2 N and/or O atoms which ismonosubstituted or disubstituted by ═O, ═S, ═NR¹ or ═NOR¹.

T is furthermore particularly preferably, for example, piperidin-1-yl,pyrrolidin-1-yl, pyridyl, morpholin-4-yl, piperazin-1-yl, pyrazin-1-yl,1,3-oxazolidin-3-yl, 2H-pyridazin-2-yl, azepan-1-yl,2-azabicyclo[2.2.2]octan-2-yl, pyrazol-2-yl or 1,2-dihydropyrazol-2-yl,each of which is monosubstituted or disubstituted by ═O, ═NR¹, ═S or═NOR¹.

In a further preferred embodiment,

-   W is —(CH₂)_(n)CONH(CH₂)_(n)— or    —(CH₂)_(n)S(O)_(m)(CH₂)_(n)CONH(CH₂)_(n)—,-   Y is 1,4-piperidyl,-   T is pyridyl,-   m is 0, 1 or 2, and-   n is 0, 1 or 2.

D is preferably an aromatic carbocyclic or heterocyclic ring having from0 to 4 N, O and/or S atoms which is unsubstituted or monosubstituted orpolysubstituted by Hal, A, OR¹, N(R¹)₂, NO₂, CN, COOR¹ or CON(R¹)₂,where the aromatic carbocyclic ring is, for example, phenyl or naphthyl,and the aromatic heterocyclic ring is, for example, as defined foraromatic radicals under Het.

D is, in particular, phenyl, pyrrolyl, furyl, thiophenyl, pyridinyl,pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, imidazolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl or triazinyl,each of which is unsubstituted or monosubstituted or polysubstituted byHal, A, OR², N(R²)₂, NO₂, CN, COOR² or CON(R²)₂.

D is furthermore particularly preferably phenyl, pyrrolyl, furyl,thiophenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl,imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl,tetrazolyl or triazinyl, each of which is unsubstituted ormonosubstituted or polysubstituted by Hal, A, OR¹, N(R¹)₂, NO₂, CN,COOR¹ or CON(R¹)₂.

In a further embodiment, D is preferably an aromatic carbocyclic orheterocyclic ring having from 0 to 4 N, O and/or S atoms which ismonosubstituted or polysubstituted by Hal, where the carbocyclic ringis, for example, phenyl or naphthyl, and the aromatic heterocyclic ringis, for example, as defined for aromatic radicals under Het.

In a further embodiment, D is particularly preferably phenyl, pyrrolyl,furyl, thiophenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl,pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl ortriazinyl, each of which is monosubstituted or polysubstituted by Hal.

D is very particularly preferably phenyl, thiophenyl or pyridinyl, eachof which is monosubstituted or polysubstituted by Hal.

X and X′ are preferably each, independently of one another, for example,H, F, Cl, OH, methoxy, ethoxy, amino, methylamino, dimethylamino, nitro,CN, carboxyl, methoxycarbonyl or aminocarbonyl.

X and X′ are, in particular, H.

Het-diyl is preferably furandiyl, thiophenediyl, pyrrolediyl,imidazolediyl, pyrazolediyl, oxazolediyl, isoxazolediyl, thiazolediyl,isothiazolediyl, pyridinediyl, pyrimidinediyl, pyrrolidinediyl orpiperidinediyl, each of which is unsubstituted or monosubstituted ordisubstituted by R^(2′), where R^(2′) is preferably H or alkyl having 1,2, 3, 4, 5 or 6 carbon atoms.

In a further embodiment, Y is preferably phenylene or piperidinediyl,each of which is unsubstituted or monosubstituted or disubstituted by A,Br, Cl or F.

The compounds of the formula I can have one or more centres of chiralityand therefore occur in various stereoisomeric forms. The formula Icovers all these forms.

Accordingly, the invention relates, in particular, to the compounds ofthe formula I in which at least one of the said radicals has one of thepreferred meanings indicated above. Some preferred groups of compoundscan be expressed by the following sub-formulae la to lac, which conformto the formula I and in which the radicals not denoted in greater detailare as defined under the formula I, but in which

-   in Ia D is an aromatic carbocyclic or heterocyclic ring having from    0 to 4 N, O and/or S atoms which is unsubstituted or monosubstituted    or polysubstituted by Hal, A, OR¹, N(R¹)₂, NO₂, CN, COOR¹ or    CON(R¹)₂;-   in Ib D is phenyl, pyrrolyl, furyl, thiophenyl, pyridinyl,    pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, imidazolyl,    oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl    or triazinyl, each of which is unsubstituted or monosubstituted or    polysubstituted by Hal, A, OR², N(R²)₂, NO₂, CN, COOR² or CON(R²)₂;-   in Ic D is phenyl, pyrrolyl, furyl, thiophenyl, pyridinyl,    pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, imidazolyl,    oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl    or triazinyl, each of which is unsubstituted or monosubstituted or    polysubstituted by Hal, A, OR¹, N(R¹)₂, NO₂, CN, COOR¹ or CON(R¹)₂;-   in Id D is an aromatic carbocyclic or heterocyclic ring having from    0 to 4 N, O and/or S atoms which is monosubstituted or    polysubstituted by Hal;-   in Ie D is phenyl, pyrrolyl, furyl, thiophenyl, pyridinyl,    pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, imidazolyl,    oxazolyl, isoxazolyl, thiazolyl, isothiazolyl or triazinyl, each of    which is monosubstituted or polysubstituted by Hal;-   in If D is phenyl, thiophenyl or pyridinyl, each of which is    monosubstituted or polysubstituted by Hal;-   in Ig X and X′ are H;-   in Ih R² is H, A or —[C(R¹)₂]_(n)—Ar′;-   in Ii Y is phenylene which is unsubstituted or monosubstituted or    disubstituted by A, Br, Cl or F;-   in Ij Ar is phenyl, naphthyl or biphenyl, each of which is    unsubstituted or monosubstituted, disubstituted or trisubstituted by    Hal, A, OR¹, N(R¹)₂, NO₂, CN, COOR¹, CON(R¹)₂, NR¹COA, NR¹CON(R¹)₂,    NR¹SO₂A, COR¹, SO₂N(R¹)₂, S(O)_(m)A, —[C(R¹)₂]_(n)—COOR¹ or    —O—[C(R¹)₂]_(o)—COOR¹;-   in Ik T is a monocyclic saturated or unsaturated carbocyclic or    heterocyclic ring having 1 or 2 N and/or O atoms which is    unsubstituted or monosubstituted or disubstituted by ═O, ═S, ═NR¹,    ═NOR¹, ═N—CN, ═N—NO₂, ═NCOR¹, ═NCOOR¹, ═NOCOR¹, A, Hal and/or    S(O)_(m)A;-   in II T is a monocyclic saturated or unsaturated heterocyclic ring    having 1 or 2 N and/or O atoms which is unsubstituted or    monosubstituted or disubstituted by ═O, ═S, ═NR¹ or ═NOR¹;-   in Im T is piperidin-1-yl, pyrrolidin-1-yl, pyridyl, morpholin-4-yl,    piperazin-1-yl, pyrazin-1-yl, 1,3-oxazolidin-3-yl,    2H-pyridazin-2-yl, azepan-1-yl, 2-azabicyclo[2.2.2]octan-2-yl,    pyrazol-2-yl or 1,2-dihydropyrazol-2-yl, each of which is    unsubstituted or monosubstituted or disubstituted by ═O, ═NR¹, ═S,    ═NOR¹, A, Hal and/or S(O)_(m)A,-    or phenyl, which may be monosubstituted, disubstituted or    trisubstituted by A, Hal and/or S(O)_(m)A;-   in In T is 2-oxopiperidin-1-yl, 2-oxopyrrolidin-1-yl,    2-oxo-1H-pyridin-1-yl, 3-oxomorpholin-4-yl, 4-oxo-1H-pyridin-1-yl,    2,6-dioxopiperidin-1-yl, 2-oxopiperazin-1-yl, 2-oxopyrazin-1-yl,    2,6-dioxopiperazin-1-yl, 2,5-dioxopyrrolidin-1-yl,    2-oxo-1,3-oxazolidin-3-yl, 3-oxo-2H-pyridazin-2-yl,    2-caprolactam-1-yl (=2-oxoazepan-1-yl),    2-hydroxy-6-oxopiperazin-1-yl, 2-azabicyclo[2.2.2]octan-3-on-2-yl,    2-methoxy-6-oxopiperazin-1-yl, 5,6-dihydro-1H-pyrimidin-2-oxo-1-yl,    2-iminopiperidin-1-yl, 2-iminopyrrolidin-1-yl,    2-imino-1H-pyridin-1-yl, 3-iminomorpholin-4-yl,    4-imino-1H-pyridin-1-yl, 2,6-diiminopiperidin-1-yl,    2-iminopiperazin-1-yl, 2,6-diiminopiperazin-1-yl,    2,5-diiminopyrrolidin-1-yl, 2-imino-1,3-oxazolidin-3-yl,    3-imino-2H-pyridazin-2-yl, 2-iminoazepan-1-yl,    2-hydroxy-6-iminopiperazin-1-yl, 2-methoxy-6-iminopiperazin-1-yl or    pyridyl, and the corresponding hydroxyimino, alkoxyimino and thioxo    derivatives, or phenyl, which may be monosubstituted, disubstituted    or trisubstituted by A, Hal and/or S(O)_(m)A;-   in Io T is 2-oxopiperidin-1-yl, 2-oxopyrrolidin-1-yl,    2-oxo-1H-pyridin-1-yl, 3-oxomorpholin-4-yl, 4-oxo-1H-pyridin-1-yl,    2,6-dioxopiperidin-1-yl, 2-oxopiperazin-1-yl,    2,6-dioxo-piperazin-1-yl, 2-oxopyrazin-1-yl,    2,5-dioxopyrrolidin-1-yl, 2-oxo-1,3-oxazolidin-3-yl,    3-oxo-2H-pyridazin-2-yl, 2-caprolactam-1-yl (=2-oxoazepan-1-yl),    2-hydroxy-6-oxopiperazin-1-yl, 2-azabicyclo[2.2.2]octan-3-on-2-yl,    2-methoxy-6-oxopiperazin-1-yl, 5,6-dihydro-1H-pyrimidin-2-oxo-1-yl,    2-iminopiperidin-1-yl, 2-iminopyrrolidin-1-yl or pyridyl,-    or phenyl, which may be monosubstituted, disubstituted or    trisubstituted by A, Hal and/or S(O)_(m)A;-   in Ip Ar is phenyl which is unsubstituted or monosubstituted or    disubstituted by Hal or A;-   in Iq Het-diyl is furandiyl, thiophenediyl, pyrrolediyl,    imidazolediyl, pyrazolediyl, oxazolediyl, isoxazolediyl,    thiazolediyl, isothiazolediyl, pyridinediyl, pyrimidinediyl,    pyrrolidinediyl or piperidinediyl, each of which is unsubstituted or    monosubstituted or disubstituted by R^(2′),    -   R^(2′) is H or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms;-   in Ir D is an aromatic carbocyclic or heterocyclic ring having from    0 to 4 N, O and/or S atoms which is unsubstituted or monosubstituted    or polysubstituted by Hal, A, OR¹, N(R¹)₂, NO₂, CN, COOR¹ or    CON(R¹)₂,    -   X and X′ are H,    -   W is —[C(R²)₂]_(n)CONR²[C(R²)₂]_(n)—,        —[C(R²)₂]_(n)NR²CO[C(R²)₂]_(n)—, —[C(R²)₂]_(n)O[C(R²)₂]_(n)—,        —[C(R²)₂]_(n)NR²[C(R²)₂]_(n)—,        —[C(R²)₂]_(n)O[C(R²)₂]_(n)CONR²[C(R²)₂]_(n)—,        —[C(R²)₂]_(n)NR²[C(R²)₂]_(n)CONR²[C(R²)₂]_(n)—,        —[C(R²)₂]_(n)NR²COO[C(R²)₂]_(n)— or        —[C(R²)₂]_(n)S(O)_(m)[C(R²)₂]_(n)CONR²[C(R²)₂]_(n)—,    -   R² is H, A or —[C(R¹)₂]_(n)—Ar′,    -   Y is alkylene, cycloalkylene, Het-diyl or Ar-diyl,    -   Ar-diyl is phenylene or biphenylene, each of which is        unsubstituted or monosubstituted or disubstituted by R^(2′),    -   Het-diyl is furandiyl, thiophenediyl, pyrrolediyl,        imidazolediyl, pyrazolediyl, oxazolediyl, isoxazolediyl,        thiazolediyl, isothiazolediyl, pyridinediyl, pyrimidinediyl,        pyrrolidinediyl or piperidinediyl, each of which is        unsubstituted or monosubstituted or disubstituted by R^(2′),    -   R² is H or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms,    -   Ar′ is phenyl,    -   T is a monocyclic saturated or unsaturated carbocyclic or        heterocyclic ring having 1 or 2 N and/or O atoms which is        unsubstituted or monosubstituted or disubstituted by ═O, ═S,        ═NR¹, ═NOR¹, ═N—CN, ═N—NO₂, ═NCOR¹, ═NCOOR¹, ═NOCOR¹, A, Hal        and/or S(O)_(m)A,    -   R¹ is H or A,    -   A is unbranched or branched alkyl having 1-10 carbon atoms, and        1-7 H atoms may be replaced by F;-   in Is D is phenyl, pyrrolyl, furyl, thiophenyl, pyridinyl,    pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, imidazolyl,    oxazolyl, isoxazolyl, thiazolyl, isothiazolyl or triazinyl, each of    which is monosubstituted or polysubstituted by Hal,    -   X and X′ are H,    -   W is —[C(R²)₂]_(n)CONR²[C(R²)₂]_(n)—,        —[C(R²)₂]_(n)NR²CO[C(R²)₂]_(n)—, —[C(R²)₂]_(n)O[C(R²)₂]_(n)—,        —[C(R²)₂]_(n)NR²[C(R²)₂]_(n)—,        —[C(R²)₂]_(n)O[C(R²)₂]_(n)CONR²[C(R²)₂]_(n)—,        —[C(R²)₂]_(n)NR²[C(R²)₂]_(n)CONR²[C(R²)₂]_(n)—,        —[C(R²)₂]_(n)NR²COO[C(R²)₂]_(n)— or        —[C(R²)₂]_(n)S(O)_(m)[C(R²)₂]_(n)CONR²[C(R²)₂]_(n)—,    -   R² is H, A or —[C(R¹)₂]_(n)—Ar′,    -   Ar′ is phenyl,    -   Y is phenylene or piperidinediyl, each of which is unsubstituted        or monosubstituted or disubstituted by A, Br, Cl or F,    -   T is a monocyclic saturated or unsaturated carbocyclic or        heterocyclic ring having 1 or 2 N and/or O atoms which is        unsubstituted or monosubstituted or disubstituted by ═O, ═S,        ═NR¹, ═NOR¹, ═N—CN, ═N—NO₂, ═NCOR¹, ═NCOOR¹, ═NOCOR¹, A, Hal        and/or S(O)_(m)A,    -   R¹ is H or A,    -   A is unbranched or branched alkyl having 1-10 carbon atoms, and        1-7 H atoms may be replaced by F;-   in It D is phenyl, pyrrolyl, furyl, thiophenyl, pyridinyl,    pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, imidazolyl,    oxazolyl, isoxazolyl, thiazolyl, isothiazolyl or triazinyl, each of    which is monosubstituted or polysubstituted by Hal,    -   X and X′ are H,    -   W is —[C(R²)₂]_(n)CONR²[C(R²)₂]_(n)—,        —[C(R²)₂]_(n)NR²CO[C(R²)₂]_(n)—, —[C(R²)₂]_(n)O[C(R²)₂]_(n)—,        —[C(R²)₂]_(n)NR²[C(R²)₂]_(n)—,        —[C(R²)₂]_(n)O[C(R²)₂]_(n)CONR²[C(R²)₂]_(n)—,        —[C(R²)₂]_(n)NR²[C(R²)₂]_(n)CONR²[C(R²)₂]_(n)—,        —[C(R²)₂]_(n)NR²COO[C(R²)₂]_(n)— or        —[C(R²)₂]_(n)S(O)_(m)[C(R²)₂]_(n)CONR²[C(R²)₂]_(n)—,    -   R² is H, A or —[C(R¹)₂]_(n)—Ar′,    -   Ar′ is phenyl,    -   Y is phenylene or piperidinediyl, each of which is unsubstituted        or monosubstituted or disubstituted by A, Br, Cl or F,    -   T is 2-oxopiperidin-1-yl, 2-oxopyrrolidin-1-yl,        2-oxo-1H-pyridin-1-yl, 3-oxomorpholin-4-yl,        4-oxo-1H-pyridin-1-yl, 2,6-dioxopiperidin-1-yl,        2-oxopiperazin-1-yl, 2,6-dioxo-piperazin-1-yl,        2-oxopyrazin-1-yl, 2,5-dioxopyrrolidin-1-yl,        2-oxo-1,3-oxazolidin-3-yl, 3-oxo-2H-pyridazin-2-yl,        2-caprolactam-1-yl (=2-oxoazepan-1-yl),        2-hydroxy-6-oxopiperazin-1-yl,        2-azabicyclo[2.2.2]octan-3-on-2-yl,        2-methoxy-6-oxopiperazin-1-yl,        5,6-dihydro-1H-pyrimidin-2-oxo-1-yl, 2-iminopiperidin-1-yl,        2-iminopyrrolidin-1-yl or pyridyl,    -    or phenyl, which may be monosubstituted, disubstituted or        trisubstituted by A, Hal and/or S(O)_(m)A,    -   R¹ is H or A,    -   A is unbranched or branched alkyl having 1-10 carbon atoms, and        1-7 H atoms may be replaced by F;-   in Iu D is phenyl, pyrrolyl, furyl, thiophenyl, pyridinyl,    pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, imidazolyl,    oxazolyl, isoxazolyl, thiazolyl, isothiazolyl or triazinyl, each of    which is monosubstituted or polysubstituted by Hal,    -   X and X′ are H,    -   W is —[C(R²)₂]_(n)CONR²[C(R²)₂]_(n)— or        —[C(R²)₂]_(n)S(O)_(m)[C(R²)₂]_(n)CONR²[C(R²)₂]_(n)—,    -   R² is H, A or —[C(R¹)₂]_(n)—Ar′,    -   Ar′ is phenyl,    -   Y is phenylene or piperidinediyl, each of which is unsubstituted        or monosubstituted or disubstituted by A, Br, Cl or F,    -   T is pyridyl,    -   R¹ is H or A,    -   A is unbranched or branched alkyl having 1-10 carbon atoms, and        1-7 H atoms may be replaced by F;-   in Iv T is a monocyclic saturated or unsaturated heterocyclic ring    having 1 or 2 N and/or O atoms which is monosubstituted or    disubstituted by ═O, ═S, ═NR¹ or ═NOR¹;-   in Iw T is piperidin-1-yl, pyrrolidin-1-yl, pyridyl, morpholin-4-yl,    piperazin-1-yl, pyrazin-1-yl, 1,3-oxazolidin-3-yl,    2H-pyridazin-2-yl, azepan-1-yl, 2-azabicyclo[2.2.2]octan-2-yl,    pyrazol-2-yl or 1,2-dihydropyrazol-2-yl, each of which is    monosubstituted or disubstituted by ═O, ═NR¹, ═S or ═NOR¹;-   in Ix T is 2-oxopiperidin-1-yl, 2-oxopyrrolidin-1-yl,    2-oxo-1H-pyridin-1-yl, 3-oxomorpholin-4-yl, 4-oxo-1H-pyridin-1-yl,    2,6-dioxopiperidin-1-yl, 2-oxopiperazin-1-yl, 2-oxopyrazin-1-yl,    2,6-dioxopiperazin-1-yl, 2,5-dioxopyrrolidin-1-yl,    2-oxo-1,3-oxazolidin-3-yl, 3-oxo-2H-pyridazin-2-yl,    2-caprolactam-1-yl (=2-oxoazepan-1-yl),    2-hydroxy-6-oxopiperazin-1-yl, 2-azabicyclo[2.2.2]octan-3-on-2-yl,    2-methoxy-6-oxopiperazin-1-yl, 5,6-dihydro-1H-pyrimidin-2-oxo-1-yl,    2-iminopiperidin-1-yl, 2-iminopyrrolidin-1-yl,    2-imino-1H-pyridin-1-yl, 3-iminomorpholin-4-yl,    4-imino-1H-pyridin-1-yl, 2,6-diiminopiperidin-1-yl,    2-iminopiperazin-1-yl, 2,6-diiminopiperazin-1-yl,    2,5-diiminopyrrolidin-1-yl, 2-imino-1,3-oxazolidin-3-yl,    3-imino-2H-pyridazin-2-yl, 2-iminoazepan-1-yl,    2-hydroxy-6-iminopiperazin-1-yl or 2-methoxy-6-iminopiperazin-1-yl,-    and the corresponding hydroxyimino, alkoxyimino and thioxo    derivatives;-   in Iy T is 2-oxopiperidin-1-yl, 2-oxopyrrolidin-1-yl,    2-oxo-1H-pyridin-1-yl, 3-oxomorpholin-4-yl, 4-oxo-1H-pyridin-1-yl,    2,6-dioxopiperidin-1-yl, 2-oxopiperazin-1-yl,    2,6-dioxo-piperazin-1-yl, 2-oxopyrazin-1-yl,    2,5-dioxopyrrolidin-1-yl, 2-oxo-1,3-oxazolidin-3-yl,    3-oxo-2H-pyridazin-2-yl, 2-caprolactam-1-yl (=2-oxoazepan-1-yl),    2-hydroxy-6-oxopiperazin-1-yl, 2-azabicyclo[2.2.2]octan-3-on-2-yl,    2-methoxy-6-oxopiperazin-1-yl, 5,6-dihydro-1H-pyrimidin-2-oxo-1-yl,    2-iminopiperidin-1-yl or 2-iminopyrrolidin-1-yl;-   in Iz D is an aromatic carbocyclic or heterocyclic ring having from    0 to 4 N, O and/or S atoms which is unsubstituted or monosubstituted    or polysubstituted by Hal, A, OR¹, N(R¹)₂, NO₂, CN, COOR¹ or    CON(R¹)₂,    -   X and X′ are H,    -   W is —[C(R²)₂]_(n)CONR²[C(R²)₂]_(n)—,        —[C(R²)₂]_(n)NR²CO[C(R²)₂]_(n)—, —[C(R²)₂]_(n)O[C(R²)₂]_(n)—,        —[C(R²)₂]_(n)NR²[C(R²)₂]_(n)—,        —[C(R²)₂]_(n)O[C(R²)₂]_(n)CONR²[C(R²)₂]_(n)—,        —[C(R²)₂]_(n)NR²[C(R²)₂]_(n)CONR²[C(R²)₂]_(n)—,        —[C(R²)₂]_(n)NR²COO[C(R²)₂]_(n)— or        —[C(R²)₂]_(n)S(O)_(m)[C(R²)₂]_(n)CONR²[C(R²)₂]_(n)—,    -   R² is H, A or —[C(R¹)₂]_(n)—Ar′,    -   Y is alkylene, cycloalkylene, Het-diyl or Ar-diyl,    -   Ar-diyl is phenylene or biphenylene, each of which is        unsubstituted or monosubstituted or disubstituted by R^(2′),    -   Het-diyl is furandiyl, thiophenediyl, pyrrolediyl,        imidazolediyl, pyrazolediyl, oxazolediyl, isoxazolediyl,        thiazolediyl, isothiazolediyl, pyridinediyl, pyrimidinediyl,        pyrrolidinediyl or piperidinediyl, each of which is        unsubstituted or monosubstituted or disubstituted by R^(2′),    -   R^(2′) is H or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms,    -   Ar′ is phenyl,    -   T is a monocyclic saturated or unsaturated carbocyclic or        heterocyclic ring having 1 or 2 N and/or O atoms which is        monosubstituted or disubstituted by ═O, ═S, ═NR¹, ═NOR¹, ═N—CN,        ═N—NO₂, ═NCOR¹, ═NCOOR¹ or ═NOCOR¹,    -   R¹ is H or A,    -   A is unbranched or branched alkyl having 1-10 carbon atoms, and        1-7 H atoms may be replaced by F;-   in Iab D is phenyl, pyrrolyl, furyl, thiophenyl, pyridinyl,    pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, imidazolyl,    oxazolyl, isoxazolyl, thiazolyl, isothiazolyl or triazinyl, each of    which is monosubstituted or polysubstituted by Hal,    -   X and X′ are H,    -   W is —[C(R²)₂]_(n)CONR²[C(R²)₂]_(n)—,        —[C(R²)₂]_(n)NR²CO[C(R²)₂]_(n)—, —[C(R²)₂]_(n)O[C(R²)₂]_(n)—,        —[C(R²)₂]_(n)NR²[C(R²)₂]_(n)—,        —[C(R²)₂]_(n)[C(R²)₂]_(n)CONR²[C(R²)₂]_(n)—,        —[C(R²)₂]_(n)NR²[C(R²)₂]_(n)CONR²[C(R²)₂]_(n)—,        —[C(R²)₂]_(n)NR²COO[C(R²)₂]_(n)— or        —[C(R²)₂]_(n)S(O)_(m)[C(R²)₂]_(n)CONR²[C(R²)₂]_(n)—,    -   R² is H, A or —[C(R¹)₂]_(n)—Ar′,    -   Ar′ is phenyl,    -   Y is phenylene or piperidinediyl, each of which is unsubstituted        or monosubstituted or disubstituted by A, Br, Cl or F,    -   T is a monocyclic saturated or unsaturated carbocyclic or        heterocyclic ring having 1 or 2 N and/or O atoms which is        monosubstituted or disubstituted by ═O, ═S, ═NR¹, ═NOR¹, ═N—CN,        ═N—NO₂, ═NCOR¹, ═NCOOR¹ or ═NOCOR¹,    -   R¹ is H or A,    -   A is unbranched or branched alkyl having 1-10 carbon atoms, and        1-7 H atoms may be replaced by F;-   in Iac D is phenyl, pyrrolyl, furyl, thiophenyl, pyridinyl,    pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, imidazolyl,    oxazolyl, isoxazolyl, thiazolyl, isothiazolyl or triazinyl, each of    which is monosubstituted or polysubstituted by Hal,    -   X and X′ are H,    -   W is —[C(R²)₂]_(n)CONR²[C(R²)₂]_(n)—,        —[C(R²)₂]_(n)NR²CO[C(R²)₂]_(n)—, —[C(R²)₂]_(n)O[C(R²)₂]_(n)—,        —[C(R²)₂]_(n)NR²[C(R²)₂]_(n)—,        —[C(R²)₂]_(n)O[C(R²)₂]_(n)CONR²[C(R²)₂]_(n)—,        —[C(R²)₂]_(n)NR²[C(R²)₂]_(n)CONR²[C(R²)₂]_(n)—,        —[C(R²)₂]_(n)NR²COO[C(R²)₂]_(n)— or        —[C(R²)₂]_(n)S(O)_(m)[C(R²)₂]_(n)CONR²[C(R²)₂]_(n)—,    -   R² is H, A or —[C(R¹)₂]_(n)—Ar′,    -   Ar′ is phenyl,    -   Y is phenylene or piperidinediyl, each of which is unsubstituted        or monosubstituted or disubstituted by A, Br, Cl or F,    -   T is 2-oxopiperidin-1-yl, 2-oxopyrrolidin-1-yl,        2-oxo-1H-pyridin-1-yl, 3-oxomorpholin-4-yl,        4-oxo-1H-pyridin-1-yl, 2,6-dioxopiperidin-1-yl,        2-oxopiperazin-1-yl, 2,6-dioxopiperazin-1-yl, 2-oxopyrazin-1-yl,        2,5-dioxo-pyrrolidin-1-yl, 2-oxo-1,3-oxazolidin-3-yl,        3-oxo-2H-pyridazin-2-yl, 2-caprolactam-1-yl (=2-oxoazepan-1-yl),        2-hydroxy-6-oxopiperazin-1-yl,        2-azabicyclo[2.2.2]octan-3-on-2-yl,        2-methoxy-6-oxopiperazin-1-yl,        5,6-dihydro-1H-pyrimidin-2-oxo-1-yl, 2-iminopiperidin-1-yl or        2-iminopyrrolidin-1-yl,    -   R¹ is H or A,    -   A is unbranched or branched alkyl having 1-10 carbon atoms, and        1-7 H atoms may be replaced by F;        and pharmaceutically usable derivatives, solvates and        stereoisomers thereof, including mixtures thereof in all ratios.

The invention relates, in particular, to the following compounds of theformula I:

-   2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[4-(3-oxomorpholin-4-yl)phenyl]acetamide,-   2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[3-methyl-4-(3-oxomorpholin-4-yl)phenyl]acetamide,-   2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[4-(2-oxopyridin-1-yl)phenyl]acetamide,-   2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[4-(2-oxopyrrolidin-1-yl)phenyl]acetamide,-   2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[3-methyl-4-(2-oxopyrrolidin-1-yl)phenyl]acetamide,-   2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[4-(2-oxopyrazin-1-yl)phenyl]acetamide,-   2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[4-(2-iminopyrrolidin-1-yl)phenyl]acetamide,-   2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[4-(2-iminopiperidin-1-yl)phenyl]acetamide,-   2-(5-chlorothiophen-2-yl)-5-[4-(2-oxopiperidin-1-yl)phenoxymethyl]-1H-benzimidazole,-   2-(5-chlorothiophen-2-yl)-5-[4-(2-oxopiperidin-1-yl)phenoxy]-1H-benzimidazole,-   2-(5-chlorothiophen-2-yl)-5-[4-(2-oxopiperidin-1-yl)phenylamino]-1H-benzimidazole,-   2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[4-(3-oxomorpholin-4-yl)phenyl]valeramide,-   2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[4-(3-oxomorpholin-4-yl)phenyl]-3-phenylpropionamide,-   2-[2-(4-chlorophenyl)-1H-benzimidazol-5-yl]-N-[4-(3-oxomorpholin-4-yl)phenyl]acetamide,-   2-[2-(4-chlorophenyl)-1H-benzimidazol-5-yl]-N-[3-methyl4-(3-oxomorpholin-4-yl)phenyl]acetamide,-   2-[2-(5-chloropyridin-2-yl)-1H-benzimidazol-5-yl]-N-[4-(3-oxomorpholin-4-yl)phenyl]acetamide,-   2-[2-(5-chloropyridin-2-yl)-1H-benzimidazol-5-yl]-N-[3-methyl-4-(3-oxomorpholin-yl)phenyl]acetamide,-   2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[4-(2-oxopiperidin-1-yl)benzyl]acetamide,-   2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yloxy]-N-[4-(3-oxomorpholin-4-yl)phenyl]acetamide,-   2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yloxy]-N-[4-(3-oxomorpholin-4-yl)phenyl]valeramide,-   2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yloxy]-N-[4-(2-oxopiperidin-1-yl)benzyl]acetamide,-   2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[4-(3-oxomorpholin-4-yl)benzyl]acetamide,-   1-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[4-(2-oxopiperidin-1-yl)benzyl]formamide,-   N-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-4-(2-oxopiperidin-1-yl)benzamide,-   N-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-ylmethyl]-N-[4-(2-oxopiperidin-1-yl)benzyl]amine,-   2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-ylamino]-N-[4-(3-oxomorpholin-4-yl)phenyl]acetamide,-   2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-(2′-methylsulfonylbiphenyl-4-yl)acetamide,-   2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)acetamide,    and pharmaceutically usable derivatives, solvates and stereoisomers    thereof, including mixtures thereof in all ratios.

The compounds of the formula I and also the starting materials for thepreparation are, in addition, prepared by methods known per se, asdescribed in the literature (for example in the standard works, such asHouben-Weyl, Methoden der organischen Chemie [Methods of OrganicChemistry], Georg-Thieme-Verlag, Stuttgart), to be precise underreaction conditions which are known and suitable for the said reactions.Use can also be made here of variants which are known per se, but arenot mentioned here in greater detail.

If desired, the starting materials can also be formed in situ so thatthey are not isolated from the reaction mixture, but instead areimmediately converted further into the compounds of the formula I.

The starting compounds of the formulae II and III are generally known.If they are novel, they can, however, be prepared by methods known perse.

All compounds of the following formula VI (where R═H or methyl; n=3, 4or 5) can be synthesised in accordance with the following scheme:

For example, synthesis of 1-(4-amino-2-methylphenyl)piperidine-2-thione:

Alternative synthesis:

Synthesis of the phenylpiperidinethione unit without a methyl group:

Compounds of the formula I can preferably be obtained by reactingcompounds of the formula II with compounds of the formula III.

The reaction is generally carried out in an inert solvent.

Examples of suitable inert solvents are hydrocarbons, such as hexane,petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons,such as trichloroethylene, 1,2-dichloroethane, tetrachloromethane,chloroform or dichloromethane, alcohols, such as methanol, ethanol,isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such asdiethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane;glycol ethers, such as ethylene glycol monomethyl or monoethyl ether orethylene glycol dimethyl ether (diglyme); ketones, such as acetone orbutanone; amides, such as acetamide, dimethylacetamide ordimethylformamide (DMF); nitriles, such as acetonitrile; sulfoxides,such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids,such as formic acid or acetic acid; nitro compounds, such asnitromethane or nitrobenzene; esters, such as ethyl acetate, or mixturesof the said solvents.

In the compounds of the formula II, L is preferably Cl, Br, I or a freeor reactively modified OH group, such as, for example, an activatedester, an imidazolide or alkylsulfonyloxy having 1-6 carbon atoms(preferably methylsulfonyloxy or trifluoromethylsulfonyloxy) orarylsulfonyloxy having 6-10 carbon atoms (preferably phenyl- orp-tolylsulfonyloxy).

Radicals of this type for activation of the carboxyl group in typicalacylation reactions are described in the literature (for example in thestandard works, such as Houben-Weyl, Methoden der organischen Chemie[Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart).Activated esters are advantageously formed in situ, for example throughaddition of HOBt or N-hydroxysuccinimide.

The reaction is generally carried out in an inert solvent, in thepresence of an acid-binding agent, preferably an organic base, such asDIPEA, triethylamine, dimethylaniline, pyridine, N-methylmorpholine orquinoline, or an excess of the carboxyl component of the formula II.

It may also be favourable to add an alkali or alkaline earth metalhydroxide, carbonate or bicarbonate or another salt of a weak acid ofthe alkali or alkaline earth metals, preferably of potassium, sodium,calcium or caesium.

Depending on the conditions used, the reaction time is between a fewminutes and 14 days, and the reaction temperature is between about −30°and 140°, normally between −10° and 90°, in particular between about 0°and about 70°.

Suitable inert solvents are those mentioned above.

Compounds of the formula I can furthermore be obtained by liberatingcompounds of the formula I from one of their functional derivatives bytreatment with a solvolysing or hydrogenolysing agent.

Preferred starting materials for the solvolysis or hydrogenolysis arethose which conform to the formula I, but contain correspondingprotected amino and/or hydroxyl groups instead of one or more free aminoand/or hydroxyl groups, preferably those which carry an amino-protectinggroup instead of an H atom bonded to an N atom, in particular thosewhich carry an R′—N group, in which R′ is an amino-protecting group,instead of an HN group, and/or those which carry an hydroxyl-protectinggroup instead of the H atom of an hydroxyl group, for example thosewhich conform to the formula I, but carry a —COOR″ group, in which R″ isan hydroxyl-protecting group, instead of a —COOH group.

Preferred starting materials are also the oxadiazole derivatives, whichcan be converted into the amidino compounds.

It is also possible for a plurality of—identical or different—protectedamino and/or hydroxyl groups to be present in the molecule of thestarting material. If the protecting groups present are different fromone another, they can in many cases be cleaved off selectively.

The term “amino-protecting group” is known in general terms and relatesto groups which are suitable for protecting (blocking) an amino groupagainst chemical reactions, but which are easy to remove after thedesired chemical reaction has been carried out elsewhere in themolecule. Typical of such groups are, in particular, unsubstituted orsubstituted acyl, aryl, aralkoxymethyl or aralkyl groups. Since theamino-protecting groups are removed after the desired reaction (orreaction sequence), their type and size is furthermore not crucial;however, preference is given to those having 1-20, in particular 1-8,carbon atoms. The term “acyl group” is to be understood in the broadestsense in connection with the present process. It includes acyl groupsderived from aliphatic, araliphatic, aromatic or heterocyclic carboxylicacids or sulfonic acids, and, in particular, alkoxy-carbonyl,aryloxycarbonyl and especially aralkoxycarbonyl groups. Examples of suchacyl groups are alkanoyl, such as acetyl, propionyl and butyryl;aralkanoyl, such as phenylacetyl; aroyl, such as benzoyl and tolyl;aryloxyalkanoyl, such as POA; alkoxycarbonyl, such as methoxycarbonyl,ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC (tert-butoxycarbonyl)and 2-iodoethoxycarbonyl; aralkoxycarbonyl, such as CBZ(“carbobenzoxy”), 4-methoxybenzyloxycarbonyl and FMOC; and arylsulfonyl,such as Mtr. Preferred amino-protecting groups are BOC and Mtr,furthermore CBZ, Fmoc, benzyl and acetyl.

The term “hydroxyl-protecting group” is likewise known in general termsand relates to groups which are suitable for protecting a hydroxyl groupagainst chemical reactions, but are easily removable after the desiredchemical reaction has been carried out elsewhere in the molecule.Typical of such groups are the above-mentioned unsubstituted orsubstituted aryl, aralkyl or acyl groups, furthermore also alkyl groups.The nature and size of the hydroxyl-protecting groups are not crucialsince they are removed again after the desired chemical reaction orreaction sequence; preference is given to groups having 1-20, inparticular 1-10, carbon atoms. Examples of hydroxyl-protecting groupsare, inter alia, benzyl, 4-methoxybenzyl, p-nitrobenzoyl,p-toluenesulfonyl, tert-butyl and acetyl, where benzyl and tert-butylare particularly preferred.

The compounds of the formula I are liberated from their functionalderivatives—depending on the protecting group used—for example usingstrong acids, advantageously using TFA or perchloric acid, but alsousing other strong inorganic acids, such as hydrochloric acid orsulfuric acid, strong organic carboxylic acids, such as trichloroaceticacid, or sulfonic acids, such as benzene- or p-toluenesulfonic acid. Thepresence of an additional inert solvent is possible, but is not alwaysnecessary. Suitable inert solvents are preferably organic, for examplecarboxylic acids, such as acetic acid, ethers, such as tetrahydrofuranor dioxane, amides, such as DMF, halogenated hydrocarbons, such asdichloromethane, furthermore also alcohols, such as methanol, ethanol orisopropanol, and water. Mixtures of the above-mentioned solvents arefurthermore suitable. TFA is preferably used in excess without additionof a further solvent, and perchloric acid is preferably used in the formof a mixture of acetic acid and 70% perchloric acid in the ratio 9:1.The reaction temperatures for the cleavage are advantageously betweenabout 0 and about 50°, preferably between 15 and 30° (room temperature).

The BOC, OBut and Mtr groups can, for example, preferably be cleaved offusing TFA in dichloromethane or using approximately 3 to 5N HCl indioxane at 15-30°, and the FMOC group can be cleaved off using anapproximately 5 to 50% solution of dimethylamine, diethylamine orpiperidine in DMF at 15-30°.

Protecting groups which can be removed hydrogenolytically (for exampleCBZ, benzyl or the liberation of the amidino group from its oxadiazolederivative) can be cleaved off, for example, by treatment with hydrogenin the presence of a catalyst (for example a noble-metal catalyst, suchas palladium, advantageously on a support, such as carbon). Suitablesolvents here are those indicated above, in particular, for example,alcohols, such as methanol or ethanol, or amides, such as DMF. Thehydrogenolysis is generally carried out at temperatures between about 0and 100° and pressures between about 1 and 200 bar, preferably at20-30°, and 1-10 bar hydrogenolysis of the CBZ group succeeds well, forexample, on 5 to 10% Pd/C in methanol or using ammonium formate (insteadof hydrogen) on Pd/C in methanol/DMF at 20-30°.

Examples of suitable inert solvents are hydrocarbons, such as hexane,petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons,such as trichloroethylene, 1,2-dichloroethane, tetrachloromethane,trifluoromethylbenzene, chloroform or dichloromethane; alcohols, such asmethanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol;ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF)or dioxane; glycol ethers, such as ethylene glycol monomethyl ormonoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones,such as acetone or butanone; amides, such as acetamide,dimethylacetamide, N-methylpyrrolidone (NMP) or dimethylformamide (DMF);nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide(DMSO); carbon disulfide; carboxylic acids, such as formic acid oracetic acid; nitro compounds, such as nitromethane or nitrobenzene;esters, such as ethyl acetate, or mixtures of the said solvents.

Esters can be saponified, for example, using acetic acid or using NaOHor KOH in water, water/THF or water/dioxane, at temperatures between 0and 100°.

Free amino groups can furthermore be acylated in a conventional mannerusing an acid chloride or anhydride or alkylated using an unsubstitutedor substituted alkyl halide or reacted with CH₃—C(═NH)—OEt,advantageously in an inert solvent, such as dichloromethane or THFand/or in the presence of a base, such as triethylamine or pyridine, attemperatures between −60 and +30°.

A base of the formula I can be converted into the associatedacid-addition salt using an acid, for example by reaction of equivalentamounts of the base and the acid in an inert solvent, such as ethanol,followed by evaporation. Suitable acids for this reaction are, inparticular, those which give physiologically acceptable salts. Thus, itis possible to use inorganic acids, for example sulfuric acid, nitricacid, hydrohalic acids, such as hydrochloric acid or hydrobromic acid,phosphoric acids, such as orthophosphoric acid, or sulfamic acid,furthermore organic acids, in particular aliphatic, alicyclic,araliphatic, aromatic or heterocyclic monobasic or polybasic carboxylic,sulfonic or sulfuric acids, for example formic acid, acetic acid,propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinicacid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaricacid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinicacid, isonicotinic acid, methane- or ethanesulfonic acid,ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonicacid, p-toluenesulfonic acid, naphthalenemono- and -disulfonic acids,and laurylsulfuric acid. Salts with physiologically unacceptable acids,for example picrates, can be used for the isolation and/or purificationof the compounds of the formula I.

On the other hand, compounds of the formula I can be converted into thecorresponding metal salts, in particular alkali metal or alkaline earthmetal salts, or into the corresponding ammonium salts using bases (forexample sodium hydroxide, potassium hydroxide, sodium carbonate orpotassium carbonate). It is also possible to use physiologicallyacceptable organic bases, such as, for example, ethanolamine.

Compounds of the formula I according to the invention may be chiralowing to their molecular structure and may accordingly occur in variousenantiomeric forms. They can therefore exist in racemic or in opticallyactive form.

Since the pharmaceutical activity of the racemates or stereoisomers ofthe compounds according to the invention may differ, it may be desirableto use the enantiomers. In these cases, the end product or even theintermediates can be separated into enantiomeric compounds by chemicalor physical measures known to the person skilled in the art or evenemployed as such in the synthesis.

In the case of racemic amines, diastereomers are formed from the mixtureby reaction with an optically active resolving agent. Examples ofsuitable resolving agents are optically active acids, such as the R andS forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid,mandelic acid, malic acid, lactic acid, suitable N-protected amino acids(for example N-benzoylproline) or N-benzenesulfonylproline), or thevarious optically active camphorsulfonic acids. Also advantage ischromatographic enantiomer resolution with the aid of an opticallyactive resolving agent (for example dinitrobenzoylphenylglycine,cellulose triacetate or other derivatives of carbohydrates or chirallyderivatised methacrylate polymers immobilised on silica gel). Examplesof suitable eluents for this purpose are aqueous or alcoholic solventmixtures, such as, for example, hexane/isopropanol/acetonitrile, forexample in the ratio 82:15:3.

The invention furthermore relates to the use of compounds of the formulaI and/or their physiologically acceptable salts for the preparation of amedicament (pharmaceutical preparation), in particular by non-chemicalmethods. They can be converted here into a suitable dosage form togetherwith at least one solid, liquid and/or semiliquid excipient or assistantand, if desired, in combination with one or more further activeingredients.

The invention furthermore relates to medicaments comprising at least onecompound of the formula I and/or its pharmaceutically usablederivatives, solvates and stereoisomers, including mixtures thereof inall ratios, and optionally excipients and/or assistants.

These preparations can be used as medicaments in human or veterinarymedicine. Suitable excipients are organic or inorganic substances whichare suitable for enteral (for example oral), parenteral or topicaladministration and do not react with the novel compounds, for examplewater, vegetable oils, benzyl alcohols, alkylene glycols, polyethyleneglycols, glycerol triacetate, gelatin, carbohydrates, such as lactose orstarch, magnesium stearate, talc or vaseline. Suitable for oraladministration are, in particular, tablets, pills, coated tablets,capsules, powders, granules, syrups, juices or drops, suitable forrectal administration are suppositories, suitable for parenteraladministration are solutions, preferably oil-based or aqueous solutions,furthermore suspensions, emulsions or implants, and suitable for topicalapplication are ointments, creams or powders or also as nasal sprays.The novel compounds may also be lyophilised and the resultantlyophilisates used, for example, to prepare injection preparations. Thepreparations indicated may be sterilised and/or comprise assistants,such as lubricants, preservatives, stabilisers and/or wetting agents,emulsifying agents, salts for modifying the osmotic pressure, buffersubstances, colorants and flavours and/or a plurality of further activeingredients, for example one or more vitamins.

The compounds of the formula I and their physiologically acceptablesalts can be used for combating thromboembolic diseases, such asthrombosis, myocardial infarction, arteriosclerosis, inflammation,apoplexia, angina pectoris, restenosis after angioplasty, claudicatiointermittens, migraines, tumours, tumour diseases and/or tumourmetastases.

In general, the substances according to the invention are preferablyadministered in doses between about 1 and 500 mg, in particular between5 and 100 mg, per dosage unit. The daily dose is preferably betweenabout 0.02 and 10 mg/kg of body weight. However, the specific dose foreach patient depends on a wide variety of factors, for example on theefficacy of the specific compound employed, on the age, body weight,general state of health, sex, on the diet, on the time and method ofadministration, on the excretion rate, medicament combination andseverity of the particular disease to which the therapy applies. Oraladministration is preferred.

The invention furthermore relates to medicaments comprising at least onecompound of the formula I and/or its pharmaceutically usablederivatives, solvates and stereoisomers, including mixtures thereof inall ratios, and at least one further medicament active ingredient.

The invention also relates to a set (kit) consisting of separate packsof

-   (a) an effective amount of a compound of the formula I and/or its    pharmaceutically usable derivatives, solvates and stereoisomers,    including mixtures thereof in all ratios, and-   (b) an effective amount of a further medicament active ingredient.

The set comprises suitable containers, such as boxes, individualbottles, bags or ampoules. The set may, for example, comprise separateampoules each containing an effective amount of a compound of theformula I and/or its pharmaceutically usable derivatives, solvates andstereoisomers, including mixtures thereof in all ratios, and aneffective amount of a further medicament active ingredient in dissolvedor lyophilised form.

The invention furthermore relates to the use of compounds of the formulaI and/or their pharmaceutically usable derivatives, solvates andstereoisomers, including mixtures thereof in all ratios, for thepreparation of a medicament for the treatment of thromboses, myocardialinfarction, arteriosclerosis, inflammation, apoplexia, angina pectoris,restenosis after angioplasty, claudicatio intermittens, migraine,tumours, tumour diseases and/or tumour metastases, in combination withat least one further medicament active ingredient.

Above and below, all temperatures are given in ° C. In the followingexamples, ‘conventional work-up’ means that water is added if necessary,the pH is adjusted, if necessary, to between 2 and 10, depending on theconstitution of the end product, the mixture is extracted with ethylacetate or dichloromethane, the phases are separated, the organic phaseis dried over sodium sulfate and evaporated, and the product is purifiedby chromatography on silica gel and/or by crystallisation. Rf values onsilica gel; eluent:ethyl acetate/methanol 9:1.

Mass spectrometry (MS):EI (electron impact ionisation) M⁺

-   -   FAB (fast atom bombardment) (M+H)⁺    -   ESI (electrospray ionisation) (M+H)⁺ (unless stated otherwise)

EXAMPLE 1

Preparation of an Amine Unit.

10 g (48.95 mmol) of 1-(4-amino-2-methylphenyl)piperidin-2-one areheated to the boil in 70 ml of anhydrous toluene together with 9.9 g(24.48 mmol) of 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane2,4-disulfide (Lawesson's reagent). After 40 minutes, the solvent isremoved, and the residue is taken up in dichloromethane (DCM)/1 Maqueous hydrochloric acid. After repeated washing with DCM, a pH of 12is set using conc. sodium hydroxide solution. Extraction with DCM,drying over Na₂SO₄ and evaporation of the solvent give 9.25 g (41.98mmol) of 1-(4-amino-2-methylphenyl)piperidine-2-thione.

EXAMPLE 2

Preparation of an Amine Unit:

2.1 15 g (78.8 mmol) of 1-(4-aminophenyl)piperidin-2-one are heated tothe boil together with 16.0 g (39.5 mmol) of2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide(Lawesson's reagent) in 100 ml of anhydrous toluene. After 45 minutes,the solvent is evaporated, and the residue is taken up indichloromethane and 2 N HCl. The aqueous phase is extracted three timeswith dichloromethane and adjusted to a pH of 12 using conc. NaOH.Extraction with dichloromethane, drying over sodium sulfate andevaporation of the solvent give 1-(4-aminophenyl)piperidine-2-thione asa colourless solid, ESI 207.

2.2 1.25 ml (20.0 mmol) of iodomethane are added to a solution of 3.74 g(18.1 mmol) of 1-(4-aminophenyl)piperidine-2-thione in 30 ml of acetone,and the mixture is stirred at room temperature for 48 hours. Thereaction mixture is evaporated, giving1-(4-aminophenyl)-6-methylsulfanyl-2,3,4,5-tetrahydropyridinium iodideas a brownish solid; ESI 221. 2.3 3.5 ml (25 mmol) of triethylamine areadded to a solution of 2.68 g (12.1 mmol) of1-(4-aminophenyl)-6-methylsulfanyl-2,3,4,5-tetrahydro-pyridinium iodideand 1.01 g (12.1 mmol) of O-methylhydroxylammonium chloride in 30 ml ofethanol, and the mixture is stirred at room temperature for 20 hours.The reaction mixture is evaporated and taken up in water, and theresultant precipitate is filtered off, giving1-(4-aminophenyl)peperidin-2-one O-methyl oxime as a colourless solid;ESI 220.

EXAMPLE 3

Preparation of2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[4-(3-oxomorpholin-4-yl)phenyl]acetamide(“AA”)

3.1 3.89 g (20.5 mmol) of sodium disulfite are added to a solution of3.00 g (20.5 mmol) of 2-chlorothiophene-5-carbaldehyde and 3.98 g (20.5mmol) of ethyl 3,4-diaminophenylacetate in 30 ml of1-methyl-pyrrolidone, and the mixture is stirred at 110° C. for 18hours. Water is added to the reaction mixture, which is extracted withdichloromethane. The organic phase is dried using sodium sulfate andevaporated, giving ethyl[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]acetate as a brown oil(ESI 321), which is employed without further purification for the nextreaction.

3.2 34.7 ml of aqueous 1 N sodium hydroxide solution are added to asolution of 10.1 g (about 20.5 mmol) of ethyl[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]acetate in 70 ml ofmethanol, and the mixture is stirred at room temperature for 3 days. Thereaction mixture is evaporated, and the residue is taken up in 25 ml ofwater. A pH of 4.5 is set by addition of conc. hydrochloric acid. Theresultant precipitate is filtered off, washed with water and dried,giving [2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]acetic acid as ayellowish solid; ESI 293.

3.3 139 mg (0.445 mmol) of2-(1H-benzotriazol-1-yl)-1,1,3,3-tetra-methyluronium tetrafluoroborate(TBTU) are added to a solution of 100 mg (0.342 mmol) of[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]acetic acid and 65.7 mg(0.342 mmol) of 4-(4-aminophenyl)morpholin-3-one in 2 ml ofdimethylformamide (DMF), and the mixture is stirred at room temperaturefor 18 hours. Saturated aqueous sodium hydrogencarbonate solution isadded to the reaction mixture, and the resultant precipitate is filteredoff, washed with water and dried, giving2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[4-(3-oxomorpholin-4-yl)phenyl]acetamideas a brownish solid; ESI 467.

An analogous reaction gives

-   2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[4-(2-oxo-piperidin-1-yl)phenyl]acetamide,    ESI 465.

An analogous reaction of[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-carboxylic acid with

-   4-(4-amino-2-methylphenyl)morpholin-3-one,-   4-(4-aminophenyl)morpholin-3-one,    gives the compounds-   N-[3-methyl4-(3-oxomorpholin-4-yl)phenyl]-2-(5-chlorothiophen-2-yl)-1H-benzimidazole-5-carboxamide,    ESI 467;-   N-[4-(3-oxomorpholin-4-yl)phenyl]-2-(5-chlorothiophen-2-yl)-1H-benzimidazole-5-carboxamide,    ESI 453.

An analogous reaction gives the following compounds:

-   2-[2-(5-bromothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[4-(3-oxomorpholin-4-yl)phenyl]acetamide,    m.p. 2500 (decomposition), ESI 511, 513;-   2-[2-(5-bromothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[4-(2-oxopiperidin-1-yl)phenyl]acetamide,    m.p. 2600 (decomposition), ESI 509, 511;-   2-[2-(5-bromothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[4-(2-oxopyridin-1-yl)phenyl]acetamide,    m.p. 2500 (decomposition), ESI 505, 507;-   2-[2-(5-bromothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[3-methyl-4-(3-oxomorpholin-4-yl)phenyl]acetamide,    m.p. 200°(decomposition), ESI 525, 527.

EXAMPLE 4

4.1 Analogously to Example 3, reaction of

-   2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-ylacetic acid    with-   4-(4-amino-2-methylphenyl)morpholin-3-one,-   1-(4-aminophenyl)pyridin-2-one,-   1-(4-aminophenyl)pyrrolidin-2-one,-   1-(4-amino-2-methylphenyl)pyrrolidin-2-one,-   1-(4-aminophenyl)pyrazin-2-one,-   1-(4-aminophenyl)-2-iminopyrrolidine,-   1-(4-aminophenyl)-2-iminopiperidine,-   2′-methylsulfonylbiphenyl-4-ylamine,-   1-(pyridin4-yl)piperidin-4-ylmethylamine,-   4-(3-oxomorpholin-4-yl)benzylamine,-   4-(2-oxopiperidin-1-yl)benzylamine,    gives the following compounds:-   2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[3-methyl-4-(3-oxomorpholin-4-yl)phenyl]acetamide    (“AB”), ESI 481;-   2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[4-(2-oxopyridin-1-yl)phenyl]acetamide    (“AC”), ESI 461;-   2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[4-(2-oxopyrrolidin-1-yl)phenyl]acetamide,    ESI 451;-   2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[3-methyl-4-(2-oxopyrrolidin-1-yl)phenyl]acetamide,    ESI 465;-   2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[4-(2-oxopyrazin-1-yl)phenyl]acetamide,    ESI 462;-   2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[4-(2-iminopyrrolidin-1-yl)phenyl]acetamide,    formate, ESI 450;-   2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[4-(2-iminopiperidin-1-yl)phenyl]acetamide,    formate, ESI 464;-   2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-(2′-methylsulfonylbiphenyl4-yl)acetamide,    ESI 522-   2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)acetamide    (“AX”), ESI 466

-   2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[4-(3-oxomorpholin-4-yl)benzyl]acetamide,    ESI 481;-   2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[4-(2-oxopiperidin-1-yl)benzyl]acetamide.

“AX” is converted into the hydrochloride by standard methods using HCIin propanol.

4.2 Analogously to the following reaction scheme, reaction of

-   2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-ylvaleric acid    with-   4-(4-aminophenyl)morpholin-3-one,    gives the compound-   2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[4-(3-oxomorpholin-4-yl)phenyl]valeramide,    ESI 509,

4.3 Analogously to Example 3, reaction of

-   2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl-3-phenylpropionic    acid    with 4-(4-aminophenyl)morpholin-3-one,    gives the compound-   2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[4-(3-oxomorpholin-4-yl)phenyl]-3-phenylpropionamide,    ESI 557.

4.4 An analogous reaction of2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-ylvaleric acid with1-(4-aminophenyl)-2-iminopiperidine gives the compound

-   2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[4-(2-imino-piperidin-1-yl)phenyl]valeramide,    formate, ESI 506.

4.5 An analogous reaction gives the following compounds:

-   2-[2-(5-bromothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[4-(2-oxopiperidin-1-yl)benzyl]acetamide,    m.p. 200° (decomposition), ESI 523, 525;-   2-[2-(5-bromothiophen-2-yl)-1H-benzimidazol-5-yl]-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)acetamide,    m.p. 200°, ESI 510, 512.

EXAMPLE 5

5.1 Analogously to Example 3, reaction of

-   2-(4-chlorophenyl)-1H-benzimidazol-5-ylacetic acid    with-   4-(4-aminophenyl)morpholin-3-one,-   4-(4-amino-2-methylphenyl)morpholin-3-one,    gives the compounds-   2-[2-(4-chlorophenyl)-1H-benzimidazol-5-yl]-N-[4-(3-oxomorpholin-4-yl)phenyl]acetamide,    ESI 461;-   2-[2-(4-chlorophenyl)-1H-benzimidazol-5-yl]-N-[3-methyl-4-(3-oxomorpholin-4-yl)phenyl]acetamide.

5.2 Analogously to Example 3, reaction of

-   2-(5-chloropyridin-2-yl)-1H-benzimidazol-5-ylacetic acid    with-   4-(4-aminophenyl)morpholin-3-one,-   4-(4-amino-2-methylphenyl)morpholin-3-one,    gives the compounds-   2-[2-(5-chloropyridin-2-yl)-1H-benzimidazol-5-yl]-N-[4-(3-oxomorpholin-4-yl)phenyl]acetamide,-   2-[2-(5-chloropyridin-2-yl)-1H-benzimidazol-5-yl]-N-[3-methyl-4-(3-oxomorpholin-4-yl)phenyl]acetamide.

EXAMPLE 6

6.1 Analogously to Example 3, reaction of2-(4-chlorophenyl)-1H-benzimidazol-5-ylacetic acid with

-   1-(4-aminophenyl)pyrrolidin-2-one O-methyl oxime,-   1-(4-amino-2-methylphenyl)pyrrolidin-2-one O-methyl oxime,    gives the compounds-   2-[2-(4-chlorophenyl)-1H-benzimidazol-5-yl]-N-[4-(N-methoxy-2-iminopyrrolidin-1-yl)phenyl]acetamide,-   2-[2-(4-chlorophenyl)-1H-benzimidazol-5-yl]-N-[3-methyl4-(N-methoxy-2-iminopyrrolidin-1-yl)phenyl]acetamide.

6.2 300 mg of Raney nickel and 5 mg of acetic acid are added to asolution of 50 mg of2-[2-(4-chlorophenyl)-1H-benzimidazol-5-yl]-N-[4-(N-methoxy-2-iminopyrrolidin-1-yl)phenyl]acetamidein 10 ml of methanol, and the mixture is hydrogenated at roomtemperature and atmospheric pressure. The catalyst is filtered off, andthe filtrate is evaporated, giving2-[2-(4-chlorophenyl)-1H-benzimidazol-5-yl]-N-[4-(2-iminopyrrolidin-1-yl)phenyl]acetamide.

EXAMPLE 7

Preparation of2-(5-chlorothiophen-2-yl)-5-[4-(2-oxopiperidin-1-yl)-phenoxymethyl]-1H-benzimidazoleis carried out analogously to the following scheme:

EXAMPLE 8

Preparation of2-(5-chlorothiophen-2-yl)-5-[4-(2-oxopiperidin-1-yl)-phenoxy]-1H-benzimidazole,ESI 424, is carried out analogously to the following scheme:

EXAMPLE 9 Preparation of2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yloxy]-N-[4-(3-oxomorpholin-4-yl)phenyl]acetamide,ESI 483, is carried out analogously to the following scheme:

An analogous reaction gives the compounds

-   2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yloxy]-N-[4-(3-oxomorpholin-4-yl)phenyl]valeramide,    ESI 525

-   2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yloxy]-N-[4-(2-oxopiperidin-1-yl)phenyl]acetamide,-   2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yloxy]-N-[4-(2-oxopiperidin-1-yl)benzyl]acetamide,    ESI 495;-   2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yloxy]-N-[4-(2-oxo-2H-pyrazin-1-yl)phenyl]acetamide,    ESI 478;-   2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yloxy]-N-[4-(2-oxopiperidin-1-yl)phenyl]acetamide,    ESI 481;-   2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yloxy]-N-[4-(2-iminopiperidin-1-yl)phenyl]acetamide,    ESI 480;-   2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yloxy]-N-[3-methyl-4-(3-oxomorpholin-4-yl)phenyl]acetamide,    hydrochloride, ESI 497,-   2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yloxy]-N-[3-fluoro-4-(3-oxomorpholin-4-yl)phenyl]valeramide,    ESI 501.

EXAMPLE 10

Preparation ofN-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl-methyl]-4-(2-oxopiperidin-1-yl)benzamide,ESI 465, is carried out analogously to the following scheme:

An analogous reaction gives

-   N-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-ylmethyl]-2-[4-(3-oxomorpholin-4-yl)phenyl]acetamide,    ESI 481;-   N-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-2-[4-(3-oxomorpholin-4-yl)phenyl]acetamide,    ESI 467.

EXAMPLE 11

Preparation ofN-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl-methyl]-N-[4-(2-oxopiperidin-1-yl)benzyl]amine,ESI 451, is carried out analogously to the following scheme:

EXAMPLE 12

Preparation of2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-ylamino]-N-[4-(3-oxomorpholin-4-yl)phenyl]acetamideis carried out analogously to the following scheme:

EXAMPLE 13

Preparation of1-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[4-(2-oxopiperidin-1-yl)benzyl]formamide,ESI 465, is carried out Analogously to the following scheme:

EXAMPLE 14

Preparation of2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazole-5-sulfonyl]-N-[3-methyl-4-(3-oxomorpholin-4-yl)phenyl]acetamideis carried out analogously to the following scheme:

14.1 4.25 g (30.7 mmol) of potassium-carbonate are added to a solutionof 2.65 g (15.4 mmol) of 5-chloro-2-nitroaniline and 1.66 g (1 5.4 mmol)of methyl thioglycolate in 14 ml of DMF, and the mixture is stirred atroom temperature for 18 hours. The reaction mixture is introduced intowater, and the resultant precipitate is filtered off, giving methyl(3-amino-4-nitrophenylsulfanyl)acetate as a yellow solid; ESI 243.

14.2 11.0 g of oxone are added to a suspension of 2.89 g (11.9 mmol) ofmethyl (3-amino-4-nitrophenylsulfanyl)acetate in a mixture of 25 ml ofwater and 50 ml of methanol, and the mixture is stirred at roomtemperature for 40 hours. Water is added to the reaction mixture, andthe precipitate is filtered off, giving methyl(3-amino-4-nitrobenzenesulfonyl)-acetate as a yellow solid; ESI 275.

14.3 500 mg of Raney nickel are added to a solution of 2.40 g (8.76mmol) of methyl (3-amino-4-nitrobenzenesulfonyl)acetate in 50 ml ofmethanol, and the mixture is hydrogenated at room temperature andatmospheric pressure. The catalyst is filtered off, and the filtrate isevaporated, giving methyl (3,4-diaminobenzenesulfonyl)acetate as ayellow solid; ESI 245.

14.4 747 mg (3.93 mmol) of sodium disulfite are added to a solution of1.15 g (7.86 mmol) of 2-chlorothiophene-5-carbaldehyde and 1.92 g (7.86mmol) of methyl (3,4-diaminobenzenesulfonyl)acetate in 25 ml of1-methylpyrrolidone, and the mixture is stirred at 110° C. for 18 hours.Water is added to the reaction mixture, which is extracted withdichloromethane. The organic phase is dried over sodium sulfate andevaporated. The residue is stirred with water, and the resultantprecipitate is filtered off, giving methyl[2-(5-chlorothiophen-2-yl)-1H-benzimidazole-5-sulfonyl]-acetate as abrown solid; ESI 371.

14.5 5 ml of aqueous 1 N sodium hydroxide solution are added to asolution of 1.04 g (2.81 mmol) of methyl[2-(5-chlorothiophen-2-yl)-1H-benzimidazole-5-sulfonyl]acetate in 50 mlof methanol, and the mixture is stirred at room temperature for 3 days.The reaction mixture is evaporated, and the residue is taken up inwater. A pH of 2 is set by addition of conc. hydrochloric acid. Theresultant precipitate is filtered off, washed with water and dried,giving [2-(5-chlorothiophen-2-yl)-1H-benzimidazole-5-sulfonyl]aceticacid as a brownish solid; ESI 357.

14.6 Reaction with the aniline derivative to give the end product iscarried out as described in Example 3, giving

-   2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazole-5-sulfonyl]-N-[3-methyl-4-(3-oxomorpholin-4-yl)phenyl]acetamide,    ESI 545.

The following compounds are obtained analogously:

-   2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazole-5-sulfonyl]-N-[4-(3-oxomorpholin-4-yl)phenyl]acetamide,    ESI 531;-   2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazole-5-sulfonyl]-N-[4-(2-oxopyridin-1-yl)phenyl]acetamide,    ESI 525;-   2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazole-5-sulfonyl]-N-[4-(2-oxopiperidin-1-yl)benzyl]acetamide,    ESI 543.

EXAMPLE 15

Reaction analogously to Example 3 starting from ethyl3-(3,4-diamino-phenyl)propionate (instead of ethyl3,4-diaminophenylacetate) gives the following compounds:

-   3-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[4-(3-oxomorpholin-4-yl)phenyl]propionamide    and-   3-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[3-methyl-4-(3-oxomorpholin-4-yl)phenyl]propionamide.    Pharmacological Data    Affinity to Receptors

TABLE 1 Compound No. FXa-IC₅₀ [M] TF/FVIIa-IC₅₀ [M] “AA” 2.3 × 10⁻⁷ 1.9× 10⁻⁷ “AB” 1.2 × 10⁻⁷ 1.3 × 10⁻⁷ “AC” 1.8 × 10⁻⁷ 1.3 × 10⁻⁷

The following examples relate to pharmaceutical preparations:

EXAMPLE A Injection Vials

A solution of 100 g of an active ingredient of the formula I and 5 g ofdisodium hydrogenphosphate in 3 l of bidistilled water is adjusted to pH6.5 using 2N hydrochloric acid, sterile filtered, transferred intoinjection vials, lyophilised under sterile conditions and sealed understerile conditions. Each injection vial contains 5 mg of activeingredient.

EXAMPLE B Suppositories

A mixture of 20 g of an active ingredient of the formula I with 100 g ofsoya lecithin and 1400 g of cocoa butter is melted, poured into mouldsand allowed to cool. Each suppository contains 20 mg of activeingredient.

EXAMPLE C Solution

A solution is prepared from 1 g of an active ingredient of the formulaI, 9.38 g of NaH₂PO₄.2 H₂O, 28.48 g of Na₂HPO₄.12 H₂O and 0.1 g ofbenzalkonium chloride in 940 ml of bidistilled water. The pH is adjustedto 6.8, and the solution is made up to 1 l and sterilised byirradiation. This solution can be used in the form of eye drops.

EXAMPLE D Ointment

500 mg of an active ingredient of the formula I are mixed with 99.5 g ofVaseline under aseptic conditions.

EXAMPLE E Tablets

A mixture of 1 kg of active ingredient of the formula I, 4 kg oflactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesiumstearate is pressed to give tablets in a conventional manner in such away that each tablet contains 10 mg of active ingredient.

EXAMPLE F Coated Tablets

Tablets are pressed analogously to Example E and subsequently coated ina conventional manner with a coating of sucrose, potato starch, talc,tragacanth and dye.

EXAMPLE G Capsules

2 kg of active ingredient of the formula I are introduced into hardgelatine capsules in a conventional manner in such a way that eachcapsule contains 20 mg of the active ingredient.

EXAMPLE H Ampoules

A solution of 1 kg of active ingredient of the formula I in 60 l ofbidistilled water is sterile filtered, transferred into ampoules,lyophilised under sterile conditions and sealed under sterileconditions. Each ampoule contains 10 mg of active ingredient.

1. A compound of formula

in which D is, thiophenyl, which is monosubstituted or polysubstitutedby Hal, X and X′ are H, W is —[C(R²)₂]_(n)CONR²[C(R²)₂]_(n)—, R² is H, Aor —[C(R¹)₂]_(n)—Ar′, Ar′ is phenyl, Y is phenylene, which isunsubstituted or monosubstituted or disubstituted by A, Br, Cl or F, Tis 2-oxopiperidin-1-yl, 2-oxopyrrolidin-1-yl, 2-oxo-1H-pyridin-1-yl,3-oxomorpholin-4-yl, 4-oxo-1H-pyridin-1-yl, 2,6-dioxopiperidin-1-yl,2-oxopiperazin-1-yl, 2,6-dioxopiperazin-1-yl, 2-oxopyrazin-1-yl,2,5-dioxo-pyrrolidin-1-yl, 2-oxo-1,3-oxazolidin-3-yl,3-oxo-2H-pyridazin-2-yl, 2-caprolactam-1-yl (=2-oxoazepan-1-yl),2-hydroxy-6-oxopiperazin-1-yl, 2-azabicyclo[2.2.2]octan-3-on-2-yl,2-methoxy-6-oxopiperazin-1-yl, 5,6-dihydro-1H-pyrimidin-2-oxo-1-yl,2-iminopiperidin-1-yl or 2-iminopyrrolidin-1-yl, R¹ is H, A isunbranched or branched alkyl having 1-10 carbon atoms, in which 1-7 Hatoms are optionally replaced by F, and n is 0, 1 or
 2. 2. A compoundaccording to claim 1, which is2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[4-(3-oxomorpholin-4-yl)phenyl]acetamide,2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[3-methyl-4-(3-oxomorpholin-4yl)phenyl]acetamide,2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[4-(2-oxopyridin-1-yl)phenyl]acetamide,2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[4-(2-oxopyrrolidin-1-yl)phenyl]acetamide,2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[3-methyl-4-(2-oxopyrrolidin-1-yl)phenyl]acetamide,2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[4-(2-oxopyrazin-1-yl)phenyl]acetamide,2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[4-(2-iminopyrrolidin-1-yl)phenyl]acetamide,2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[4-(2-iminopiperidin-1-yl)phenyl]acetamide,2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[4-(3-oxomorpholin-4-yl)phenyl]valeramide,2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[4-(3-oxomorpholin-4-yl)phenyl]-3-phenylpropionamide,2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[4-(3-oxomorpholin-4-yl)benzyl]acetamide,1-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[4-(2-oxopiperidin-1-yl)benzyl]formamide,3-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[4-(3-oxomorpholin-4-yl)phenyl]propionamide,3-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[3-methyl-4-(3-oxomorpholin-4-yl)phenyl]propionamide,2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[4-(2-oxopiperidin-1-yl)phenyl]acetamide,2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[4-(2-iminopiperidin-1-yl)phenyl]valeramide,2-[2-(5-bromothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[4-(3-oxomorpholin-4-yl)phenyl]acetamide,2-[2-(5-bromothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[4-(2-oxopiperidin-1-yl)phenyl]acetamide,2-[2-(5-bromothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[4-(2-oxopyridin-1-yl)phenyl]acetamide,2-[2-(5-bromothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[4-(2-oxopiperidin-1-yl)benzyl]acetamide,2-[2-(5-bromothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[3-methyl-4-(3-oxomorpholin-4-yl)phenyl]acetamide,N-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-ylmethyl]-2-[4-(3-oxomorpholin-4-yl)phenyl]acetamide,orN-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-2-[4-(3-oxomorpholin-4-yl)phenyl]acetamide.3. A process for preparing a compound according to claim 1, comprisinga) reacting a compound of formula II

 in which  L is Cl, Br, I or a free or reactively functionally modifiedOH group,  and R¹, R², D, X, X′ and n are as defined for the compound offormula I,  wherein any further OH and/or amino group present isprotected,  with a compound of formula IIIZ′-Y-T  III  in which  Z′ is NHR²[C(R²)₂]_(n)—,  and R², Y, T and n areas defined for the compound of formula I,  wherein any protecting groupis subsequently removed, b) and/or convening a radical T in a compoundof formula I into another radical T and/or  converting a base or acid ofthe compound of formula I into one of its salts.
 4. A pharmaceuticalcomposition, comprising a compound according to claim 1 and apharmaceutically acceptable carrier.
 5. A pharmaceutical compositionaccording to claim 4, further comprising another pharmaceutically activecompound other than the compound of formula I.
 6. A method for treatingthromboses, comprising administering to a subject in need thereof aneffective amount of a pharmaceutical composition according to claim 4.7. A set or kit comprising separate packs of (a) a compound according toclaim 1, and (b) a further pharmaceutically active compound other thanthe compound of formula I.
 8. A method for treating thromboses,comprising administering to a subject in need thereof an effectiveamount of a pharmaceutical composition according to claim
 5. 9. Aprocess according to claim 3, wherein converting a radical T in acompound of formula I into another radical T is achieved by converting asulfanyl compound into an imino compound, or by removing anamino-protecting group.
 10. A compound according to claim 1, which is anisolated stereoisomer of a compound of formula I.
 11. A compound offormula I,

in which D is thiophenyl, which is monosubstituted or polysubstituted byHal, X and X′ are H, W is —[C(R²)₂]_(n)CONR²[C(R²)₂]_(n)—, R² is H, A or—[C(R¹)₂]_(n)—Ar′, Ar′ is phenyl, Y is phenylene which is unsubstitutedor monosubstituted or disubstituted by A, Br, Cl or F, T is2-oxopiperidin-1-yl, 2-oxopyrrolidin-1-yl, 2-oxo-1H-pyridin-1-yl,3-oxomorpholin-4-yl, 4-oxo-1H-pyridin-1-yl, 2,6-dioxopiperidin-1-yl,2-oxopiperazin-1-yl, 2,6-dioxopiperazin-1-yl, 2-oxopyrazin-1-yl,2,5-dioxo-pyrrolidin-1-yl, 2-oxo-1,3-oxazolidin-3-yl,3-oxo-2H-pyridazin-2-yl, 2-caprolactam-1-yl (=2-oxoazepan-1-yl),2-hydroxy-6-oxopiperazin-1-yl, 2-azabicyclo[2.2.2]octan-3-on-2-yl,2-methoxy-6-oxopiperazin-1-yl, 5,6-dihydro-1H-pyrimidin-2-oxo-1-yl,2-iminopiperidin-1-yl or 2-iminopyrrolidin-1-yl, R¹ is H, A isunbranched or branched alkyl having 1-10 carbon atoms, in which 1-7 Hatoms are optionally replaced by F, n is 0,1 or 2, or a pharmaceuticallyacceptable salt thereof.
 12. A compound which is2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[4-(3-oxomorpholin-4-yl)phenyl]acetamide,2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[3-methyl-4-(3-oxomorpholin-4-yl)phenyl]acetamide,2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[4-(2-oxopyridin-1-yl)phenyl]acetamide,2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[4-(2-oxopyrrolidin-1-yl)phenyl]acetamide,2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[3-methyl-4-(2-oxopyrrolidin-1-yl)phenyl]acetamide,2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[4-(2-oxopyrazin-1-yl)phenyl]acetamide,2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[4-(2-iminopyrrolidin-1-yl)phenyl]acetamide,2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[4-(2-iminopiperidin-1-yl)phenyl]acetamide,2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[4-(3-oxomorpholin-4-yl)phenyl]valeramide,2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[4-(3-oxomorpholin-4-yl)phenyl]-3-phenylpropionamide,2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[4-(2-oxopiperidin-1-yl)benzyl]acetamide,2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[4-(3-oxomorpholin-4-yl)benzyl]acetamide,1-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[4-(2-oxopiperidin-1-yl)benzyl]formamide,3-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[4-(3-oxomorpholin-4-yl)phenyl]propionamide,3-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[3-methyl-4-(3-oxomorpholin-4-yl)phenyl]propionamide,2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[4-(2-oxopiperidin-1-yl)phenyl]acetamide,2-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[4-(2-iminopiperidin-1-yl)phenyl]valeramide,2-[2-(5-bromothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[4-(3-oxomorpholin-4-yl)phenyl]acetamide,2-[2-(5-bromothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[4-(2-oxopiperidin-1-yl)phenyl]acetamide,2-[2-(5-bromothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[4-(2-oxopyridin-1-yl)phenyl]acetamide,2-[2-(5-bromothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[4-(2-oxopiperidin-1-yl)benzyl]acetamide,2-[2-(5-bromothiophen-2-yl)-1H-benzimidazol-5-yl]-N-[3-methyl-4-(3-oxomorpholin-yl)phenyl]acetamide,N-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-ylmethyl]-2-[4-(3-oxomorpholin-4-ylphenyl]acetamide,orN-[2-(5-chlorothiophen-2-yl)-1H-benzimidazol-5-yl]-2-[4-(3-oxomorpholin-4-yl)phenyl]acetamide,or a pharmaceutically acceptable salt thereof.
 13. A compound accordingto claim 11, wherein Y is phenylene, which is unsubstituted.
 14. Apharmaceutical composition, comprising a compound according to claim 11and a pharmaceutically acceptable carrier.
 15. A pharmaceuticalcomposition, comprising a compound according to claim 12 and apharmaceutically acceptable carrier.
 16. A method for treatingthromboses comprising administering to a subject in need thereof aneffective amount of a pharmaceutical composition according to claim 14.17. A method for treating thromboses comprising administering to asubject in need thereof an effective amount of a pharmaceuticalcomposition according to claim
 15. 18. A compound according to claim 11,which is an isolated stereoisomer of a compound of formula I.